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1
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Xiao Y, Jin W, Ju L, Fu J, Wang G, Yu M, Chen F, Qian K, Wang X, Zhang Y. Tracking single-cell evolution using clock-like chromatin accessibility loci. Nat Biotechnol 2025; 43:784-798. [PMID: 38724668 DOI: 10.1038/s41587-024-02241-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 04/10/2024] [Indexed: 05/18/2025]
Abstract
Single-cell chromatin accessibility sequencing (scATAC-seq) reconstructs developmental trajectory by phenotypic similarity. However, inferring the exact developmental trajectory is challenging. Previous studies showed age-associated DNA methylation (DNAm) changes in specific genomic regions, termed clock-like differential methylation loci (ClockDML). Age-associated DNAm could either result from or result in chromatin accessibility changes at ClockDML. As cells undergo mitosis, the heterogeneity of chromatin accessibility on clock-like loci is reduced, providing a measure of mitotic age. In this study, we developed a method, called EpiTrace, that counts the fraction of opened clock-like loci from scATAC-seq data to determine cell age and perform lineage tracing in various cell lineages and animal species. It shows concordance with known developmental hierarchies, correlates well with DNAm-based clocks and is complementary with mutation-based lineage tracing, RNA velocity and stemness predictions. Applying EpiTrace to scATAC-seq data reveals biological insights with clinically relevant implications, ranging from hematopoiesis, organ development, tumor biology and immunity to cortical gyrification.
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Affiliation(s)
- Yu Xiao
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China
- Department of Biological Repositories, Human Genetic Resources Preservation Center of Hubei Province, Hubei Key Laboratory of Urological Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Wan Jin
- Department of Biological Repositories, Human Genetic Resources Preservation Center of Hubei Province, Hubei Key Laboratory of Urological Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
- Euler Technology, ZGC Life Sciences Park, Beijing, China
| | - Lingao Ju
- Department of Biological Repositories, Human Genetic Resources Preservation Center of Hubei Province, Hubei Key Laboratory of Urological Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Jie Fu
- Hong Kong University of Science and Technology, Hong Kong, China
| | - Gang Wang
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China
- Department of Biological Repositories, Human Genetic Resources Preservation Center of Hubei Province, Hubei Key Laboratory of Urological Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Mengxue Yu
- Department of Biological Repositories, Human Genetic Resources Preservation Center of Hubei Province, Hubei Key Laboratory of Urological Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Fangjin Chen
- High Performance Computing Center, Peking-Tsinghua College of Life Sciences, Peking University, Beijing, China
| | - Kaiyu Qian
- Department of Biological Repositories, Human Genetic Resources Preservation Center of Hubei Province, Hubei Key Laboratory of Urological Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
- Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China
| | - Xinghuan Wang
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China.
- Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China.
- Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan, China.
| | - Yi Zhang
- Euler Technology, ZGC Life Sciences Park, Beijing, China.
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2
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Chen M, Fu R, Chen Y, Li L, Wang SW. High-resolution, noninvasive single-cell lineage tracing in mice and humans based on DNA methylation epimutations. Nat Methods 2025; 22:488-498. [PMID: 39820752 DOI: 10.1038/s41592-024-02567-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 11/19/2024] [Indexed: 01/19/2025]
Abstract
In vivo lineage tracing holds great potential to reveal fundamental principles of tissue development and homeostasis. However, current lineage tracing in humans relies on extremely rare somatic mutations, which has limited temporal resolution and lineage accuracy. Here, we developed a generic lineage-tracing tool based on frequent epimutations on DNA methylation, enabled by our computational method MethylTree. Using single-cell genome-wide DNA methylation datasets with known lineage and phenotypic labels, MethylTree reconstructed lineage histories at nearly 100% accuracy across different cell types, developmental stages, and species. We demonstrated the epimutation-based single-cell multi-omic lineage tracing in mouse and human blood, where MethylTree recapitulated the differentiation hierarchy in hematopoiesis. Applying MethylTree to human embryos, we revealed early fate commitment at the four-cell stage. In native mouse blood, we identified ~250 clones of hematopoietic stem cells. MethylTree opens the door for high-resolution, noninvasive and multi-omic lineage tracing in humans and beyond.
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Affiliation(s)
- Mengyang Chen
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- School of Life Sciences, Westlake University, Hangzhou, China
| | - Ruijiang Fu
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- School of Life Sciences, Westlake University, Hangzhou, China
- School of Science, Westlake University, Hangzhou, China
| | - Yiqian Chen
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- School of Life Sciences, Westlake University, Hangzhou, China
| | - Li Li
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China.
- School of Life Sciences, Westlake University, Hangzhou, China.
| | - Shou-Wen Wang
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China.
- School of Life Sciences, Westlake University, Hangzhou, China.
- School of Science, Westlake University, Hangzhou, China.
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3
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Ledda M, Pluchino A, Ragusa M. Exploring the Role of Genetic and Environmental Features in Colorectal Cancer Development: An Agent-Based Approach. ENTROPY (BASEL, SWITZERLAND) 2024; 26:923. [PMID: 39593869 PMCID: PMC11593013 DOI: 10.3390/e26110923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 10/22/2024] [Accepted: 10/28/2024] [Indexed: 11/28/2024]
Abstract
The complexity of issues in cancer research has led to the introduction of powerful computational tools to help experimental in vivo and in vitro methods. These tools, which typically focus on studying cell behavior and dynamic cell populations, range from systems of differential equations that are solved numerically to lattice models and agent-based simulations. In particular, agent-based models (ABMs) are increasingly used due to their ability to incorporate multi-scale features, ranging from the individual to the population level. This approach allows for the combination of statistically aggregated assumptions with individual heterogeneity. In this work, we present an ABM that simulates tumor progression in a colonic crypt, to provide an experimental in silico environment for testing results achieved in traditional laboratory research and developing alternative scenarios of tumor development. The model also allows some speculations about causal relationships in biologically inspired systems.
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Affiliation(s)
- Marco Ledda
- Dipartimento di Fisica e Astronomia Ettore Majorana, Università di Catania, 95123 Catania, Italy;
| | - Alessandro Pluchino
- Dipartimento di Fisica e Astronomia Ettore Majorana, Università di Catania, 95123 Catania, Italy;
- INFN Sezione di Catania, 95123 Catania, Italy
| | - Marco Ragusa
- Dipartimento di Scienze Biomediche e Biotecnologiche, Sezione di Biologia e Genetica, Università di Catania, 95123 Catania, Italy;
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4
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Zhu T, Tong H, Du Z, Beck S, Teschendorff AE. An improved epigenetic counter to track mitotic age in normal and precancerous tissues. Nat Commun 2024; 15:4211. [PMID: 38760334 PMCID: PMC11101651 DOI: 10.1038/s41467-024-48649-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Accepted: 05/09/2024] [Indexed: 05/19/2024] Open
Abstract
The cumulative number of stem cell divisions in a tissue, known as mitotic age, is thought to be a major determinant of cancer-risk. Somatic mutational and DNA methylation (DNAm) clocks are promising tools to molecularly track mitotic age, yet their relationship is underexplored and their potential for cancer risk prediction in normal tissues remains to be demonstrated. Here we build and validate an improved pan-tissue DNAm counter of total mitotic age called stemTOC. We demonstrate that stemTOC's mitotic age proxy increases with the tumor cell-of-origin fraction in each of 15 cancer-types, in precancerous lesions, and in normal tissues exposed to major cancer risk factors. Extensive benchmarking against 6 other mitotic counters shows that stemTOC compares favorably, specially in the preinvasive and normal-tissue contexts. By cross-correlating stemTOC to two clock-like somatic mutational signatures, we confirm the mitotic-like nature of only one of these. Our data points towards DNAm as a promising molecular substrate for detecting mitotic-age increases in normal tissues and precancerous lesions, and hence for developing cancer-risk prediction strategies.
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Affiliation(s)
- Tianyu Zhu
- CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institute for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, 200031, China
| | - Huige Tong
- CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institute for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, 200031, China
| | - Zhaozhen Du
- CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institute for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, 200031, China
| | - Stephan Beck
- Medical Genomics Group, UCL Cancer Institute, University College London, 72 Huntley Street, WC1E 6BT, London, UK
| | - Andrew E Teschendorff
- CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institute for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, 200031, China.
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5
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Koyanagi KO. Inferring chromatin accessibility during murine hematopoiesis through phylogenetic analysis. BMC Res Notes 2023; 16:222. [PMID: 37726849 PMCID: PMC10507877 DOI: 10.1186/s13104-023-06507-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 09/12/2023] [Indexed: 09/21/2023] Open
Abstract
OBJECTIVE Diversification of cell types and changes in epigenetic states during cell differentiation processes are important for understanding development. Recently, phylogenetic analysis using DNA methylation and histone modification information has been shown useful for inferring these processes. The purpose of this study was to examine whether chromatin accessibility data can help infer these processes in murine hematopoiesis. RESULTS Chromatin accessibility data could partially infer the hematopoietic differentiation hierarchy. Furthermore, based on the ancestral state estimation of internal nodes, the open/closed chromatin states of differentiating progenitor cells could be predicted with a specificity of 0.86-0.99 and sensitivity of 0.29-0.72. These results suggest that the phylogenetic analysis of chromatin accessibility could offer important information on cell differentiation, particularly for organisms from which progenitor cells are difficult to obtain.
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Affiliation(s)
- Kanako O Koyanagi
- Faculty of Information Science and Technology, Hokkaido University, Sapporo, Hokkaido, Japan.
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6
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El-Kenawi A, Berglund A, Estrella V, Zhang Y, Liu M, Putney RM, Yoder SJ, Johnson J, Brown J, Gatenby R. Elevated Methionine Flux Drives Pyroptosis Evasion in Persister Cancer Cells. Cancer Res 2023; 83:720-734. [PMID: 36480167 PMCID: PMC9978888 DOI: 10.1158/0008-5472.can-22-1002] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 09/29/2022] [Accepted: 12/02/2022] [Indexed: 12/13/2022]
Abstract
Induction of cell death represents a primary goal of most anticancer treatments. Despite the efficacy of such approaches, a small population of "persisters" develop evasion strategies to therapy-induced cell death. While previous studies have identified mechanisms of resistance to apoptosis, the mechanisms by which persisters dampen other forms of cell death, such as pyroptosis, remain to be elucidated. Pyroptosis is a form of inflammatory cell death that involves formation of membrane pores, ion gradient imbalance, water inflow, and membrane rupture. Herein, we investigate mechanisms by which cancer persisters resist pyroptosis, survive, then proliferate in the presence of tyrosine kinase inhibitors (TKI). Lung, prostate, and esophageal cancer persister cells remaining after treatments exhibited several hallmarks indicative of pyroptosis resistance. The inflammatory attributes of persisters included chronic activation of inflammasome, STING, and type I interferons. Comprehensive metabolomic characterization uncovered that TKI-induced pyroptotic persisters display high methionine consumption and excessive taurine production. Elevated methionine flux or exogenous taurine preserved plasma membrane integrity via osmolyte-mediated effects. Increased dependency on methionine flux decreased the level of one carbon metabolism intermediate S-(5'-adenosyl)-L-homocysteine, a determinant of cell methylation capacity. The consequent increase in methylation potential induced DNA hypermethylation of genes regulating metal ion balance and intrinsic immune response. This enabled thwarting TKI resistance by using the hypomethylating agent decitabine. In summary, the evolution of resistance to pyroptosis can occur via a stepwise process of physical acclimation and epigenetic changes without existing or recurrent mutations. SIGNIFICANCE Methionine enables cancer cells to persist by evading pyroptotic osmotic lysis, which leads to genome-wide hypermethylation that allows persisters to gain proliferative advantages.
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Affiliation(s)
- Asmaa El-Kenawi
- Department of Radiation Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida.,Cancer Biology and Evolution Program, H. Lee Moffitt Cancer Center, Tampa, Florida
| | - Anders Berglund
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, Florida
| | - Veronica Estrella
- Cancer Biology and Evolution Program, H. Lee Moffitt Cancer Center, Tampa, Florida.,Department of Cancer Physiology, H. Lee Moffitt Cancer Center, Tampa, Florida
| | - Yonghong Zhang
- Biostatistics and Bioinformatics Shared Resource, H. Lee Moffitt Cancer Center, Tampa, Florida
| | - Min Liu
- Proteomics and Metabolomics Core Facility, H. Lee Moffitt Cancer Center, Tampa, Florida
| | - Ryan M Putney
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, Florida
| | - Sean J Yoder
- Molecular Genomics Core Facility, H. Lee Moffitt Cancer Center, Tampa, Florida
| | - Joseph Johnson
- Analytic Microscopy Core Facility, H. Lee Moffitt Cancer Center, Tampa, Florida
| | - Joel Brown
- Cancer Biology and Evolution Program, H. Lee Moffitt Cancer Center, Tampa, Florida.,Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida
| | - Robert Gatenby
- Cancer Biology and Evolution Program, H. Lee Moffitt Cancer Center, Tampa, Florida.,Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida.,Department of Radiology, H. Lee Moffitt Cancer Center, Tampa, Florida
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7
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Heide T, Househam J, Cresswell GD, Spiteri I, Lynn C, Mossner M, Kimberley C, Fernandez-Mateos J, Chen B, Zapata L, James C, Barozzi I, Chkhaidze K, Nichol D, Gunasri V, Berner A, Schmidt M, Lakatos E, Baker AM, Costa H, Mitchinson M, Piazza R, Jansen M, Caravagna G, Ramazzotti D, Shibata D, Bridgewater J, Rodriguez-Justo M, Magnani L, Graham TA, Sottoriva A. The co-evolution of the genome and epigenome in colorectal cancer. Nature 2022; 611:733-743. [PMID: 36289335 PMCID: PMC9684080 DOI: 10.1038/s41586-022-05202-1] [Citation(s) in RCA: 59] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 08/05/2022] [Indexed: 12/13/2022]
Abstract
Colorectal malignancies are a leading cause of cancer-related death1 and have undergone extensive genomic study2,3. However, DNA mutations alone do not fully explain malignant transformation4-7. Here we investigate the co-evolution of the genome and epigenome of colorectal tumours at single-clone resolution using spatial multi-omic profiling of individual glands. We collected 1,370 samples from 30 primary cancers and 8 concomitant adenomas and generated 1,207 chromatin accessibility profiles, 527 whole genomes and 297 whole transcriptomes. We found positive selection for DNA mutations in chromatin modifier genes and recurrent somatic chromatin accessibility alterations, including in regulatory regions of cancer driver genes that were otherwise devoid of genetic mutations. Genome-wide alterations in accessibility for transcription factor binding involved CTCF, downregulation of interferon and increased accessibility for SOX and HOX transcription factor families, suggesting the involvement of developmental genes during tumourigenesis. Somatic chromatin accessibility alterations were heritable and distinguished adenomas from cancers. Mutational signature analysis showed that the epigenome in turn influences the accumulation of DNA mutations. This study provides a map of genetic and epigenetic tumour heterogeneity, with fundamental implications for understanding colorectal cancer biology.
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Affiliation(s)
- Timon Heide
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
- Computational Biology Research Centre, Human Technopole, Milan, Italy
| | - Jacob Househam
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
- Evolution and Cancer Lab, Centre for Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - George D Cresswell
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
| | - Inmaculada Spiteri
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
| | - Claire Lynn
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
| | - Maximilian Mossner
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
- Evolution and Cancer Lab, Centre for Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Chris Kimberley
- Evolution and Cancer Lab, Centre for Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, UK
| | | | - Bingjie Chen
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
| | - Luis Zapata
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
| | - Chela James
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
| | - Iros Barozzi
- Department of Surgery and Cancer, Imperial College London, London, UK
- Centre for Cancer Research, Medical University of Vienna, Vienna, Austria
| | - Ketevan Chkhaidze
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
| | - Daniel Nichol
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
| | - Vinaya Gunasri
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
- Evolution and Cancer Lab, Centre for Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Alison Berner
- Evolution and Cancer Lab, Centre for Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Melissa Schmidt
- Evolution and Cancer Lab, Centre for Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Eszter Lakatos
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
- Evolution and Cancer Lab, Centre for Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Ann-Marie Baker
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
- Evolution and Cancer Lab, Centre for Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Helena Costa
- Department of Pathology, UCL Cancer Institute, University College London, London, UK
| | - Miriam Mitchinson
- Department of Pathology, UCL Cancer Institute, University College London, London, UK
| | - Rocco Piazza
- Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
| | - Marnix Jansen
- Department of Pathology, UCL Cancer Institute, University College London, London, UK
| | - Giulio Caravagna
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
- Department of Mathematics and Geosciences, University of Triest, Triest, Italy
| | - Daniele Ramazzotti
- Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
| | - Darryl Shibata
- Department of Pathology, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
| | | | | | - Luca Magnani
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Trevor A Graham
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK.
- Evolution and Cancer Lab, Centre for Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, UK.
| | - Andrea Sottoriva
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK.
- Computational Biology Research Centre, Human Technopole, Milan, Italy.
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8
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Gabbutt C, Wright NA, Baker A, Shibata D, Graham TA. Lineage tracing in human tissues. J Pathol 2022; 257:501-512. [PMID: 35415852 PMCID: PMC9253082 DOI: 10.1002/path.5911] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 03/21/2022] [Accepted: 04/09/2022] [Indexed: 11/11/2022]
Abstract
The dynamical process of cell division that underpins homeostasis in the human body cannot be directly observed in vivo, but instead is measurable from the pattern of somatic genetic or epigenetic mutations that accrue in tissues over an individual's lifetime. Because somatic mutations are heritable, they serve as natural lineage tracing markers that delineate clonal expansions. Mathematical analysis of the distribution of somatic clone sizes gives a quantitative readout of the rates of cell birth, death, and replacement. In this review we explore the broad range of somatic mutation types that have been used for lineage tracing in human tissues, introduce the mathematical concepts used to infer dynamical information from these clone size data, and discuss the insights of this lineage tracing approach for our understanding of homeostasis and cancer development. We use the human colon as a particularly instructive exemplar tissue. There is a rich history of human somatic cell dynamics surreptitiously written into the cell genomes that is being uncovered by advances in sequencing and careful mathematical analysis lineage of tracing data. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Calum Gabbutt
- Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and the London School of Medicine and DentistryQueen Mary University of LondonLondonUK
- Centre for Evolution and CancerInstitute of Cancer ResearchSuttonUK
- London Interdisciplinary Doctoral Training Programme (LIDo)LondonUK
| | - Nicholas A Wright
- Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and the London School of Medicine and DentistryQueen Mary University of LondonLondonUK
| | - Ann‐Marie Baker
- Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and the London School of Medicine and DentistryQueen Mary University of LondonLondonUK
- Centre for Evolution and CancerInstitute of Cancer ResearchSuttonUK
| | - Darryl Shibata
- Keck School of MedicineUniversity of Southern CaliforniaLos AngelesCAUSA
| | - Trevor A Graham
- Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and the London School of Medicine and DentistryQueen Mary University of LondonLondonUK
- Centre for Evolution and CancerInstitute of Cancer ResearchSuttonUK
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9
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Sun G, Zheng W, Tan P, Zhou J, Tang W, Cao H, Liu L, Shi X, Li Z, Zhang W. Comprehensive Analysis of VCAN Expression Profiles and Prognostic Values in HCC. Front Genet 2022; 13:900306. [PMID: 35812745 PMCID: PMC9263583 DOI: 10.3389/fgene.2022.900306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Accepted: 05/13/2022] [Indexed: 12/24/2022] Open
Abstract
Background: Hepatocellular carcinoma (HCC) is the world’s most common cause of cancer death. Therefore, more molecular mechanisms need to be clarified to meet the urgent need to develop new detection and treatment strategies. Methods: We used TCGAportal, Kaplan–Meier Plotter, the Cistrome DB Toolkit Database, MExpress, GEPIA2, and other databases to discuss the expression profiles, possible biological function, and potential prognostic value of versican (VCAN) in HCC. We conducted cell experiments such as Transwell migration and invasion assays, wound healing assay, and CCK8 experiment to explore the function of VCAN in HCC. Result: We selected three HCC transcriptome databases GSE124535, GSE136247, and GSE144269 and analyzed the overexpressed genes contained in them. The overlapping genes were found by the Venn map, and two interacting network modules were found by Mcode. Module 1 was mainly related to mitosis and cell cycle, and module 2 was mainly related to EMT, angiogenesis, glycolysis, and so on. We found that the seed gene in module 2 is VCAN. Data from TCGAportal showed that compared with normal tissues, the expression of VCAN was up-regulated in HCC tissues. The patients with high expression of VCAN had shorter distant recurrence-free survival and overall survival. Multiple possible VCAN interactions had also been identified. These results revealed that the level of VCAN was higher in the subtypes of HCC with higher malignant degree and was connected to the poor prognosis. In addition, the treatment of VCAN with DNA methyltransferase inhibitors and transcription factor inhibitors may improve the prognosis of patients with HCC. Conclusion: Our findings systematically elucidated the expression profile and different prognostic values of VCAN in HCC, which may provide new therapeutic targets and potential prognostic biomarkers for HCC patients.
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Affiliation(s)
- Guangshun Sun
- Department of General Surgery, Nanjing First Hospital, The Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, China
| | - Wubin Zheng
- Department of General Surgery, Nanjing First Hospital, The Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, China
| | - Pengyu Tan
- Department of Food Science and Engineering, Nanjing Xiaozhuang University, Nanjing, China
| | - Jin Zhou
- Department of General Surgery, Nanjing First Hospital, The Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, China
| | - Weiwei Tang
- Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Transplantation, Chinese Academy of Medical Sciences, Nanjing, China
| | - Hongyong Cao
- Department of General Surgery, Nanjing First Hospital, The Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, China
- *Correspondence: Hongyong Cao, ; Li Liu, ; Xuesong Shi, ; Zhouxiao Li, ; Wenling Zhang,
| | - Li Liu
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
- *Correspondence: Hongyong Cao, ; Li Liu, ; Xuesong Shi, ; Zhouxiao Li, ; Wenling Zhang,
| | - Xuesong Shi
- Department of General Surgery, Nanjing First Hospital, The Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, China
- *Correspondence: Hongyong Cao, ; Li Liu, ; Xuesong Shi, ; Zhouxiao Li, ; Wenling Zhang,
| | - Zhouxiao Li
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Hongyong Cao, ; Li Liu, ; Xuesong Shi, ; Zhouxiao Li, ; Wenling Zhang,
| | - Wenling Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- *Correspondence: Hongyong Cao, ; Li Liu, ; Xuesong Shi, ; Zhouxiao Li, ; Wenling Zhang,
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10
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Gabbutt C, Schenck RO, Weisenberger DJ, Kimberley C, Berner A, Househam J, Lakatos E, Robertson-Tessi M, Martin I, Patel R, Clark SK, Latchford A, Barnes CP, Leedham SJ, Anderson ARA, Graham TA, Shibata D. Fluctuating methylation clocks for cell lineage tracing at high temporal resolution in human tissues. Nat Biotechnol 2022; 40:720-730. [PMID: 34980912 PMCID: PMC9110299 DOI: 10.1038/s41587-021-01109-w] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 09/28/2021] [Indexed: 02/07/2023]
Abstract
Molecular clocks that record cell ancestry mutate too slowly to measure the short-timescale dynamics of cell renewal in adult tissues. Here, we show that fluctuating DNA methylation marks can be used as clocks in cells where ongoing methylation and demethylation cause repeated 'flip-flops' between methylated and unmethylated states. We identify endogenous fluctuating CpG (fCpG) sites using standard methylation arrays and develop a mathematical model to quantitatively measure human adult stem cell dynamics from these data. Small intestinal crypts were inferred to contain slightly more stem cells than the colon, with slower stem cell replacement in the small intestine. Germline APC mutation increased the number of replacements per crypt. In blood, we measured rapid expansion of acute leukemia and slower growth of chronic disease. Thus, the patterns of human somatic cell birth and death are measurable with fluctuating methylation clocks (FMCs).
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Affiliation(s)
- Calum Gabbutt
- Evolution and Cancer Laboratory, Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- Department of Cell and Developmental Biology, University College London, London, UK
- London Interdisciplinary Doctoral Training Programme (LIDo), London, UK
| | - Ryan O Schenck
- Integrated Mathematical Oncology Department, Moffitt Cancer Center, Tampa, FL, USA
- Intestinal Stem Cell Biology Lab, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Daniel J Weisenberger
- Department of Biochemistry and Molecular Medicine, University of Southern California, Los Angeles, CA, USA
| | - Christopher Kimberley
- Evolution and Cancer Laboratory, Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Alison Berner
- Evolution and Cancer Laboratory, Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Jacob Househam
- Evolution and Cancer Laboratory, Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Eszter Lakatos
- Evolution and Cancer Laboratory, Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Mark Robertson-Tessi
- Integrated Mathematical Oncology Department, Moffitt Cancer Center, Tampa, FL, USA
| | - Isabel Martin
- Evolution and Cancer Laboratory, Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- St. Mark's Hospital, Harrow, London, UK
| | - Roshani Patel
- Evolution and Cancer Laboratory, Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- St. Mark's Hospital, Harrow, London, UK
| | - Susan K Clark
- St. Mark's Hospital, Harrow, London, UK
- Department of Surgery and Cancer, Imperial College, London, UK
| | - Andrew Latchford
- St. Mark's Hospital, Harrow, London, UK
- Department of Surgery and Cancer, Imperial College, London, UK
| | - Chris P Barnes
- Department of Cell and Developmental Biology, University College London, London, UK
| | - Simon J Leedham
- Intestinal Stem Cell Biology Lab, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK
| | | | - Trevor A Graham
- Evolution and Cancer Laboratory, Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
| | - Darryl Shibata
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
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11
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Paul KC, Binder AM, Horvath S, Kusters C, Yan Q, Rosario ID, Yu Y, Bronstein J, Ritz B. Accelerated hematopoietic mitotic aging measured by DNA methylation, blood cell lineage, and Parkinson's disease. BMC Genomics 2021; 22:696. [PMID: 34565328 PMCID: PMC8474781 DOI: 10.1186/s12864-021-08009-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Accepted: 09/13/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Aging and inflammation are important components of Parkinson's disease (PD) pathogenesis and both are associated with changes in hematopoiesis and blood cell composition. DNA methylation (DNAm) presents a mechanism to investigate inflammation, aging, and hematopoiesis in PD, using epigenetic mitotic aging and aging clocks. Here, we aimed to define the influence of blood cell lineage on epigenetic mitotic age and then investigate mitotic age acceleration with PD, while considering epigenetic age acceleration biomarkers. RESULTS We estimated epigenetic mitotic age using the "epiTOC" epigenetic mitotic clock in 10 different blood cell populations and in a population-based study of PD with whole-blood. Within subject analysis of the flow-sorted purified blood cell types DNAm showed a clear separation of epigenetic mitotic age by cell lineage, with the mitotic age significantly lower in myeloid versus lymphoid cells (p = 2.1e-11). PD status was strongly associated with accelerated epigenetic mitotic aging (AccelEpiTOC) after controlling for cell composition (OR = 2.11, 95 % CI = 1.56, 2.86, p = 1.6e-6). AccelEpiTOC was also positively correlated with extrinsic epigenetic age acceleration, a DNAm aging biomarker related to immune system aging (with cell composition adjustment: R = 0.27, p = 6.5e-14), and both were independently associated with PD. Among PD patients, AccelEpiTOC measured at baseline was also associated with longitudinal motor and cognitive symptom decline. CONCLUSIONS The current study presents a first look at epigenetic mitotic aging in PD and our findings suggest accelerated hematopoietic cell mitosis, possibly reflecting immune pathway imbalances, in early PD that may also be related to motor and cognitive progression.
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Affiliation(s)
- Kimberly C Paul
- Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
| | - Alexandra M Binder
- Population Sciences in the Pacific Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA
- Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, California, USA
| | - Steve Horvath
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Cynthia Kusters
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Qi Yan
- Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, California, USA
| | - Irish Del Rosario
- Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, California, USA
| | - Yu Yu
- Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, California, USA
| | - Jeff Bronstein
- Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Beate Ritz
- Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
- Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, California, USA
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12
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Rud D, Marjoram P, Siegmund K, Shibata D. Functional human genes typically exhibit epigenetic conservation. PLoS One 2021; 16:e0253250. [PMID: 34520456 PMCID: PMC8439480 DOI: 10.1371/journal.pone.0253250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 08/08/2021] [Indexed: 11/25/2022] Open
Abstract
Recent DepMap CRISPR-Cas9 single gene disruptions have identified genes more essential to proliferation in tissue culture. It would be valuable to translate these finding with measurements more practical for human tissues. Here we show that DepMap essential genes and other literature curated functional genes exhibit cell-specific preferential epigenetic conservation when DNA methylation measurements are compared between replicate cell lines and between intestinal crypts from the same individual. Culture experiments indicate that epigenetic drift accumulates through time with smaller differences in more functional genes. In NCI-60 cell lines, greater targeted gene conservation correlated with greater drug sensitivity. These studies indicate that two measurements separated in time allow normal or neoplastic cells to signal through conservation which human genes are more essential to their survival in vitro or in vivo.
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Affiliation(s)
- Daniel Rud
- Department of Preventive Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CA, United States of America
| | - Paul Marjoram
- Department of Preventive Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CA, United States of America
| | - Kimberly Siegmund
- Department of Preventive Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CA, United States of America
| | - Darryl Shibata
- Department of Pathology, University of Southern California, Keck School of Medicine, Los Angeles, CA, United States of America
- * E-mail:
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13
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Marca JEL, Somers WG. The Drosophila gonads: models for stem cell proliferation, self-renewal, and differentiation. AIMS GENETICS 2021. [DOI: 10.3934/genet.2014.1.55] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
AbstractThe male and female gonads of Drosophila melanogaster have developed into powerful model systems for both the study of stem cell behaviours, and for understanding how stem cell misregulation can lead to cancers. Using these systems, one is able to observe and manipulate the resident stem cell populations in vivo with a great deal of licence. The tractability of the testis and ovary also allow researchers to explore a range of cellular mechanisms, such as proliferation and polarity, as well as the influence exerted by the local environment through a host of highly-conserved signalling pathways. Importantly, many of the cellular behaviours and processes studied in the Drosophila testis and ovary are known to be disrupted, or otherwise misregulated, in human tumourigenic cells. Here, we review the mechanisms relating to stem cell behaviour, though we acknowledge there are many other fascinating aspects of gametogenesis, including the invasive behaviour of migratory border cells in the Drosophila ovary that, though relevant to the study of tumourigenesis, will unfortunately not be covered.
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Affiliation(s)
- John E. La Marca
- Department of Genetics, La Trobe University, Melbourne, VIC 3086, Australia
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14
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Wiencke JK, Zhang Z, Koestler DC, Salas LA, Molinaro AM, Christensen BC, Kelsey KT. Identification of a foetal epigenetic compartment in adult human kidney. Epigenetics 2021; 17:335-355. [PMID: 33783321 DOI: 10.1080/15592294.2021.1900027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Abstract
The mammalian kidney has extensive repair capacity; however, identifying adult renal stem cells has proven elusive. We applied an epigenetic marker of foetal cell origin (FCO) in diverse human tissues as a probe for developmental cell persistence, finding a 5.4-fold greater FCO proportion in kidney. Normal kidney FCO proportions averaged 49% with extensive interindividual variation. FCO proportions were significantly negatively correlated with immune-related gene expression and positively correlated with genes expressed in the renal medulla, including those involved in renal organogenesis (e.g., FGF2, PAX8, and HOXB7). FCO associated genes also mapped to medullary nephron segments in mouse and rat, suggesting evolutionary conservation of this cellular compartment. Renal cancer patients whose tumours contained non-zero FCO scores survived longer. The kidney appears unique in possessing substantial foetal epigenetic features. Further study of FCO-related gene methylation may elucidate regenerative regulatory programmes in tissues without apparent discrete stem cell compartments.
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Affiliation(s)
- John K Wiencke
- Department of Neurological Surgery, Institute for Human Genetics, University of California, San Francisco, CA, USA
| | - Ze Zhang
- Department of Epidemiology, Department of Pathology and Laboratory Medicine, Brown University School of Public Health, Providence, RI, USA
| | - Devin C Koestler
- Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Lucas A Salas
- Department of Epidemiology, Department of Molecular and Systems Biology, Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Lebanon, NH, USA
| | - Annette M Molinaro
- Department of Neurological Surgery, Institute for Human Genetics, University of California, San Francisco, CA, USA
| | - Brock C Christensen
- Department of Epidemiology, Department of Molecular and Systems Biology, Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Lebanon, NH, USA
| | - Karl T Kelsey
- Department of Epidemiology, Department of Pathology and Laboratory Medicine, Brown University School of Public Health, Providence, RI, USA
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15
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Wu Z, Wang Y, Wang K, Zhou D. Stochastic stem cell models with mutation: A comparison of asymmetric and symmetric divisions. Math Biosci 2021; 332:108541. [PMID: 33453222 DOI: 10.1016/j.mbs.2021.108541] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 01/05/2021] [Accepted: 01/08/2021] [Indexed: 12/12/2022]
Abstract
In order to fulfill cell proliferation and differentiation through cellular hierarchy, stem cells can undergo either asymmetric or symmetric divisions. Recent studies pay special attention to the effect of different modes of stem cell division on the lifetime risk of cancer, and report that symmetric division is more beneficial to delay the onset of cancer. The fate uncertainty of symmetric division is considered to be the reason for the cancer-delaying effect. In this paper we compare asymmetric and symmetric divisions of stem cells via studying stochastic stem cell models with mutation. Specially, by using rigorous mathematical analysis we find that both the asymmetric and symmetric models show the same statistical average, but the symmetric model shows higher fluctuation than the asymmetric model. We further show that the difference between the two models would be more remarkable for lower mutation rates. Our work quantifies the uncertainty of cell division and highlights the significance of stochasticity for distinguishing between different modes of stem cell division.
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Affiliation(s)
- Zhijie Wu
- School of Mathematical Sciences, Xiamen University, Xiamen 361005, PR China
| | - Yuman Wang
- School of Mathematical Sciences, Xiamen University, Xiamen 361005, PR China
| | - Kun Wang
- School of Mathematical Sciences, Xiamen University, Xiamen 361005, PR China
| | - Da Zhou
- School of Mathematical Sciences, Xiamen University, Xiamen 361005, PR China.
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16
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Oleksiewicz U, Machnik M. Causes, effects, and clinical implications of perturbed patterns within the cancer epigenome. Semin Cancer Biol 2020; 83:15-35. [PMID: 33359485 DOI: 10.1016/j.semcancer.2020.12.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 12/18/2020] [Accepted: 12/18/2020] [Indexed: 02/06/2023]
Abstract
Somatic mutations accumulating over a patient's lifetime are well-defined causative factors that fuel carcinogenesis. It is now clear, however, that epigenomic signature is also largely perturbed in many malignancies. These alterations support the transcriptional program crucial for the acquisition and maintenance of cancer hallmarks. Epigenetic instability may arise due to the genetic mutations or transcriptional deregulation of the proteins implicated in epigenetic signaling. Moreover, external stimulation and physiological aging may also participate in this phenomenon. The epigenomic signature is frequently associated with a cell of origin, as well as with tumor stage and differentiation, which all reflect its high heterogeneity across and within various tumors. Here, we will overview the current understanding of the causes and effects of the altered and heterogeneous epigenomic landscape in cancer. We will focus mainly on DNA methylation and post-translational histone modifications as the key regulatory epigenetic signaling marks. In addition, we will describe how this knowledge is translated into the clinic. We will particularly concentrate on the applicability of epigenetic alterations as biomarkers for improved diagnosis, prognosis, and prediction. Finally, we will also review current developments regarding epi-drug usage in clinical and experimental settings.
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Affiliation(s)
- Urszula Oleksiewicz
- Department of Cancer Immunology, Poznan University of Medical Sciences, Poznan, Poland; Department of Cancer Diagnostics and Immunology, Greater Poland Cancer Centre, Poznan, Poland.
| | - Marta Machnik
- Department of Cancer Immunology, Poznan University of Medical Sciences, Poznan, Poland; Department of Cancer Diagnostics and Immunology, Greater Poland Cancer Centre, Poznan, Poland
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17
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Paterson C, Clevers H, Bozic I. Mathematical model of colorectal cancer initiation. Proc Natl Acad Sci U S A 2020; 117:20681-20688. [PMID: 32788368 PMCID: PMC7456111 DOI: 10.1073/pnas.2003771117] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Quantifying evolutionary dynamics of cancer initiation and progression can provide insights into more effective strategies of early detection and treatment. Here we develop a mathematical model of colorectal cancer initiation through inactivation of two tumor suppressor genes and activation of one oncogene, accounting for the well-known path to colorectal cancer through loss of tumor suppressors APC and TP53 and gain of the KRAS oncogene. In the model, we allow mutations to occur in any order, leading to a complex network of premalignant mutational genotypes on the way to colorectal cancer. We parameterize the model using experimentally measured parameter values, many of them only recently available, and compare its predictions to epidemiological data on colorectal cancer incidence. We find that the reported lifetime risk of colorectal cancer can be recovered using a mathematical model of colorectal cancer initiation together with experimentally measured mutation rates in colorectal tissues and proliferation rates of premalignant lesions. We demonstrate that the order of driver events in colorectal cancer is determined primarily by the fitness effects that they provide, rather than their mutation rates. Our results imply that there may not be significant immune suppression of untreated benign and malignant colorectal lesions.
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Affiliation(s)
- Chay Paterson
- Department of Applied Mathematics, University of Washington, Seattle, WA 98195
| | - Hans Clevers
- Oncode Institute, 3521 AL Utrecht, The Netherlands;
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, 3584 CT Utrecht, The Netherlands
- University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
| | - Ivana Bozic
- Department of Applied Mathematics, University of Washington, Seattle, WA 98195;
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18
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Nam AS, Chaligne R, Landau DA. Integrating genetic and non-genetic determinants of cancer evolution by single-cell multi-omics. Nat Rev Genet 2020; 22:3-18. [PMID: 32807900 DOI: 10.1038/s41576-020-0265-5] [Citation(s) in RCA: 236] [Impact Index Per Article: 47.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/01/2020] [Indexed: 12/17/2022]
Abstract
Cancer represents an evolutionary process through which growing malignant populations genetically diversify, leading to tumour progression, relapse and resistance to therapy. In addition to genetic diversity, the cell-to-cell variation that fuels evolutionary selection also manifests in cellular states, epigenetic profiles, spatial distributions and interactions with the microenvironment. Therefore, the study of cancer requires the integration of multiple heritable dimensions at the resolution of the single cell - the atomic unit of somatic evolution. In this Review, we discuss emerging analytic and experimental technologies for single-cell multi-omics that enable the capture and integration of multiple data modalities to inform the study of cancer evolution. These data show that cancer results from a complex interplay between genetic and non-genetic determinants of somatic evolution.
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Affiliation(s)
- Anna S Nam
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.,New York Genome Center, New York, NY, USA.,Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
| | - Ronan Chaligne
- New York Genome Center, New York, NY, USA.,Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.,Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Dan A Landau
- New York Genome Center, New York, NY, USA. .,Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. .,Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA. .,Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA.
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19
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Storey K, Leder K, Hawkins-Daarud A, Swanson K, Ahmed AU, Rockne RC, Foo J. Glioblastoma Recurrence and the Role of O 6-Methylguanine-DNA Methyltransferase Promoter Methylation. JCO Clin Cancer Inform 2020; 3:1-12. [PMID: 30758983 DOI: 10.1200/cci.18.00062] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Tumor recurrence in glioblastoma multiforme (GBM) is often attributed to acquired resistance to the standard chemotherapeutic agent, temozolomide (TMZ). Promoter methylation of the DNA repair gene MGMT (O6-methylguanine-DNA methyltransferase) has been associated with sensitivity to TMZ, whereas increased expression of MGMT has been associated with TMZ resistance. Clinical studies have observed a downward shift in MGMT methylation percentage from primary to recurrent stage tumors; however, the evolutionary processes that drive this shift and more generally the emergence and growth of TMZ-resistant tumor subpopulations are still poorly understood. Here, we develop a mathematical model, parameterized using clinical and experimental data, to investigate the role of MGMT methylation in TMZ resistance during the standard treatment regimen for GBM-surgery, chemotherapy, and radiation. We first found that the observed downward shift in MGMT promoter methylation status between detection and recurrence cannot be explained solely by evolutionary selection. Next, our model suggests that TMZ has an inhibitory effect on maintenance methylation of MGMT after cell division. Finally, incorporating this inhibitory effect, we study the optimal number of TMZ doses per adjuvant cycle for patients with GBM with high and low levels of MGMT methylation at diagnosis.
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Affiliation(s)
- Katie Storey
- University of Minnesota Twin Cities, Minneapolis, MN
| | - Kevin Leder
- University of Minnesota Twin Cities, Minneapolis, MN
| | | | | | - Atique U Ahmed
- Northwestern University Feinberg School of Medicine, Chicago, IL
| | | | - Jasmine Foo
- University of Minnesota Twin Cities, Minneapolis, MN
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20
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Teschendorff AE. A comparison of epigenetic mitotic-like clocks for cancer risk prediction. Genome Med 2020; 12:56. [PMID: 32580750 PMCID: PMC7315560 DOI: 10.1186/s13073-020-00752-3] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Accepted: 06/10/2020] [Indexed: 12/19/2022] Open
Abstract
Background DNA methylation changes that accrue in the stem cell pool of an adult tissue in line with the cumulative number of cell divisions may contribute to the observed variation in cancer risk among tissues and individuals. Thus, the construction of epigenetic “mitotic” clocks that can measure the lifetime number of stem cell divisions is of paramount interest. Methods Building upon a dynamic model of DNA methylation gain in unmethylated CpG-rich regions, we here derive a novel mitotic clock (“epiTOC2”) that can directly estimate the cumulative number of stem cell divisions in a tissue. We compare epiTOC2 to a different mitotic model, based on hypomethylation at solo-WCGW sites (“HypoClock”), in terms of their ability to measure mitotic age of normal adult tissues and predict cancer risk. Results Using epiTOC2, we estimate the intrinsic stem cell division rate for different normal tissue types, demonstrating excellent agreement (Pearson correlation = 0.92, R2 = 0.85, P = 3e−6) with those derived from experiment. In contrast, HypoClock’s estimates do not (Pearson correlation = 0.30, R2 = 0.09, P = 0.29). We validate these results in independent datasets profiling normal adult tissue types. While both epiTOC2 and HypoClock correctly predict an increased mitotic rate in cancer, epiTOC2 is more robust and significantly better at discriminating preneoplastic lesions characterized by chronic inflammation, a major driver of tissue turnover and cancer risk. Our data suggest that DNA methylation loss at solo-WCGWs is significant only when cells are under high replicative stress and that epiTOC2 is a better mitotic age and cancer risk prediction model for normal adult tissues. Conclusions These results have profound implications for our understanding of epigenetic clocks and for developing cancer risk prediction or early detection assays. We propose that measurement of DNAm at the 163 epiTOC2 CpGs in adult pre-neoplastic lesions, and potentially in serum cell-free DNA, could provide the basis for building feasible pre-diagnostic or cancer risk assays. epiTOC2 is freely available from 10.5281/zenodo.2632938
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Affiliation(s)
- Andrew E Teschendorff
- CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institute for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, 200031, China. .,UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6BT, UK.
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21
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Abstract
Tracing cell lineages is fundamental for understanding the rules governing development in multicellular organisms and delineating complex biological processes involving the differentiation of multiple cell types with distinct lineage hierarchies. In humans, experimental lineage tracing is unethical, and one has to rely on natural-mutation markers that are created within cells as they proliferate and age. Recent studies have demonstrated that it is now possible to trace lineages in normal, noncancerous cells with a variety of data types using natural variations in the nuclear and mitochondrial DNA as well as variations in DNA methylation status. It is also apparent that the scientific community is on the verge of being able to make a comprehensive and detailed cell lineage map of human embryonic and fetal development. In this review, we discuss the advantages and disadvantages of different approaches and markers for lineage tracing. We also describe the general conceptual design for how to derive a lineage map for humans.
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Affiliation(s)
- Alexej Abyzov
- Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55905, USA;
| | - Flora M Vaccarino
- Child Study Center, Yale University, New Haven, Connecticut 06520, USA;
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22
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Cresswell GD, Nichol D, Spiteri I, Tari H, Zapata L, Heide T, Maley CC, Magnani L, Schiavon G, Ashworth A, Barry P, Sottoriva A. Mapping the breast cancer metastatic cascade onto ctDNA using genetic and epigenetic clonal tracking. Nat Commun 2020; 11:1446. [PMID: 32221288 PMCID: PMC7101390 DOI: 10.1038/s41467-020-15047-9] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Accepted: 02/18/2020] [Indexed: 02/06/2023] Open
Abstract
Circulating tumour DNA (ctDNA) allows tracking of the evolution of human cancers at high resolution, overcoming many limitations of tissue biopsies. However, exploiting ctDNA to determine how a patient's cancer is evolving in order to aid clinical decisions remains difficult. This is because ctDNA is a mix of fragmented alleles, and the contribution of different cancer deposits to ctDNA is largely unknown. Profiling ctDNA almost invariably requires prior knowledge of what genomic alterations to track. Here, we leverage on a rapid autopsy programme to demonstrate that unbiased genomic characterisation of several metastatic sites and concomitant ctDNA profiling at whole-genome resolution reveals the extent to which ctDNA is representative of widespread disease. We also present a methylation profiling method that allows tracking evolutionary changes in ctDNA at single-molecule resolution without prior knowledge. These results have critical implications for the use of liquid biopsies to monitor cancer evolution in humans and guide treatment.
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Affiliation(s)
- George D Cresswell
- Evolutionary Genomics and Modelling Lab, Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
| | - Daniel Nichol
- Evolutionary Genomics and Modelling Lab, Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
| | - Inmaculada Spiteri
- Evolutionary Genomics and Modelling Lab, Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
| | - Haider Tari
- Evolutionary Genomics and Modelling Lab, Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
- Glioma Lab, The Institute of Cancer Research, London, UK
| | - Luis Zapata
- Evolutionary Genomics and Modelling Lab, Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
| | - Timon Heide
- Evolutionary Genomics and Modelling Lab, Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
| | - Carlo C Maley
- Arizona Cancer Evolution Center, Biodesign Institute, Arizona State University, Tempe, AZ, USA
| | - Luca Magnani
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Gaia Schiavon
- Breast Unit, Royal Marsden Hospital, London, UK
- AstraZeneca, Oncology R&D, Cambridge, UK
| | - Alan Ashworth
- UCSF Helen Diller Family Comprehensive Cancer Center, 1450 3rd St, San Francisco, CA, 94158, USA
| | - Peter Barry
- Breast Unit, Royal Marsden Hospital, London, UK.
| | - Andrea Sottoriva
- Evolutionary Genomics and Modelling Lab, Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK.
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Mura M, Feillet C, Bertolusso R, Delaunay F, Kimmel M. Mathematical modelling reveals unexpected inheritance and variability patterns of cell cycle parameters in mammalian cells. PLoS Comput Biol 2019; 15:e1007054. [PMID: 31158226 PMCID: PMC6564046 DOI: 10.1371/journal.pcbi.1007054] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 06/13/2019] [Accepted: 04/26/2019] [Indexed: 01/12/2023] Open
Abstract
The cell cycle is the fundamental process of cell populations, it is regulated by environmental cues and by intracellular checkpoints. Cell cycle variability in clonal cell population is caused by stochastic processes such as random partitioning of cellular components to progeny cells at division and random interactions among biomolecules in cells. One of the important biological questions is how the dynamics at the cell cycle scale, which is related to family dependencies between the cell and its descendants, affects cell population behavior in the long-run. We address this question using a “mechanistic” model, built based on observations of single cells over several cell generations, and then extrapolated in time. We used cell pedigree observations of NIH 3T3 cells including FUCCI markers, to determine patterns of inheritance of cell-cycle phase durations and single-cell protein dynamics. Based on that information we developed a hybrid mathematical model, involving bifurcating autoregression to describe stochasticity of partitioning and inheritance of cell-cycle-phase times, and an ordinary differential equation system to capture single-cell protein dynamics. Long-term simulations, concordant with in vitro experiments, demonstrated the model reproduced the main features of our data and had homeostatic properties. Moreover, heterogeneity of cell cycle may have important consequences during population development. We discovered an effect similar to genetic drift, amplified by family relationships among cells. In consequence, the progeny of a single cell with a short cell cycle time had a high probability of eventually dominating the population, due to the heritability of cell-cycle phases. Patterns of epigenetic heritability in proliferating cells are important for understanding long-term trends of cell populations which are either required to provide the influx of maturing cells (such as hematopoietic stem cells) or which started proliferating uncontrollably (such as cancer cells). All cells in multicellular organisms obey orchestrated sequences of signals to ensure developmental and homeostatic fitness under a variety of external stimuli. However, there also exist self-perpetuating stem-cell populations, the function of which is to provide a steady supply of differentiated progenitors that in turn ensure persistence of organism functions. This “cell production engine” is an important element of biological homeostasis. A similar process, albeit distorted in many respects, plays a major role in cancer development; here the robustness of homeostasis contributes to difficulty in eradication of malignancy. An important role in homeostasis seems to be played by generation of heterogeneity among cell phenotypes, which then can be shaped by selection and other genetic forces. In the present paper, we present a model of a cultured cell population, which factors in relationships among related cells and the dynamics of cell growth and important proteins regulating cell division. We find that the model not only maintains homeostasis, but that it also responds to perturbations in a manner that is similar to that exhibited by the Wright-Fisher model of population genetics. The model-cell population can become dominated by the progeny of the fittest individuals, without invoking advantageous mutations. If confirmed, this may provide an alternative mode of evolution of cell populations.
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Affiliation(s)
- Marzena Mura
- System Engineering Group, Silesian University of Technology, Gliwice, Poland
- Ardigen, Krakow, Poland
- * E-mail: (MM); (MK)
| | | | - Roberto Bertolusso
- Department of Statistics, Rice University, Houston, TX, United States of America
| | | | - Marek Kimmel
- System Engineering Group, Silesian University of Technology, Gliwice, Poland
- Department of Statistics, Rice University, Houston, TX, United States of America
- Department of Bioengineering, Rice University, Houston, TX, United States of America
- * E-mail: (MM); (MK)
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DNA Methylation Clocks in Aging: Categories, Causes, and Consequences. Mol Cell 2019; 71:882-895. [PMID: 30241605 DOI: 10.1016/j.molcel.2018.08.008] [Citation(s) in RCA: 369] [Impact Index Per Article: 61.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Revised: 07/03/2018] [Accepted: 08/06/2018] [Indexed: 02/07/2023]
Abstract
Age-associated changes to the mammalian DNA methylome are well documented and thought to promote diseases of aging, such as cancer. Recent studies have identified collections of individual methylation sites whose aggregate methylation status measures chronological age, referred to as the DNA methylation clock. DNA methylation may also have value as a biomarker of healthy versus unhealthy aging and disease risk; in other words, a biological clock. Here we consider the relationship between the chronological and biological clocks, their underlying mechanisms, potential consequences, and their utility as biomarkers and as targets for intervention to promote healthy aging and longevity.
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Shibata D. Evolutionary Stem Cell Poker and Cancer Risks: The Paradox of The Large And Small Intestines. CURRENT PATHOBIOLOGY REPORTS 2019; 6:193-198. [PMID: 30713810 DOI: 10.1007/s40139-018-0176-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Purpose of review Recent studies demonstrate that normal human tissues accumulate substantial numbers of somatic mutations with aging, to levels comparable to their corresponding cancers. If mutations cause cancer, how do tissues avoid cancer when mutations are unavoidable? Recent findings The small intestines (SI) and colon accumulate similar numbers of replication errors, but SI adenocarcinoma is much rarer than colorectal cancer. Both the small and large intestines are subdivided into millions of small neighborhoods (crypts) that are maintained by small numbers of stem cells. To explain the SI cancer paradox, four fundamental evolution parameters (mutation, drift, selection, and population size) are translated to crypts. Summary The accumulations of driver mutations in a single stem cell may be analogous to an evolutionary poker game. The rarity of SI cancer may reflect that SI crypts are smaller and have fewer stem cells than the colon, which reduces the numbers of cells at risk for mutation and perhaps selection efficiency. Tissue microarchitecture may physically modulate cancer evolution by controlling the numbers of directly competing neighboring cells. A better understanding of the SI cancer paradox may illuminate how tissues naturally avoid cancers when mutations are unavoidable.
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Affiliation(s)
- Darryl Shibata
- Department of Pathology, University of Southern California Keck School of Medicine,
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26
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Plausible Links Between Metabolic Networks, Stem Cells, and Longevity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1201:355-388. [PMID: 31898793 DOI: 10.1007/978-3-030-31206-0_15] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Aging is an inevitable consequence of life, and all multicellular organisms undergo a decline in tissue and organ functions as they age. Several well-known risk factors, such as obesity, diabetes, and lack of physical activity that lead to the cardiovascular system, decline and impede the function of vital organs, ultimately limit overall life span. Over recent years, aging research has experienced an unparalleled growth, particularly with the discovery and recognition of genetic pathways and biochemical processes that control to some extent the rate of aging.In this chapter, we focus on several aspects of stem cell biology and aging, beginning with major cellular hallmarks of aging, endocrine regulation of aging and its impact on stem cell compartment, and mechanisms of increased longevity. We then discuss the role of epigenetic modifications associated with aging and provide an overview on a most recent search of antiaging modalities.
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Abstract
Cancer stem cells, sometimes referred to as tumor initiating cells, play pivotal roles in tumor initiation, progression, metastasis, resistance to therapy, and relapse. Understanding how these populations of cells expand in response to a host of conditions is critical in determining effective cancer therapeutics. A defining feature of cancer stem cells is the ability to switch between modes of quiescence and symmetric/asymmetric division to protect and conserve the population, this feature is traditionally reserved for normal adult stem cell populations. Understanding how the core cell cycle machinery responds to external cues to drive symmetric/asymmetric division vs. quiescence will reveal fundamental information about how cancer stem cell populations survive and expand. This chapter will describe methods to study the cell cycle dynamics in brain cancer stem cell populations and how they compare to the other populations in a tumor.
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Affiliation(s)
- Ingrid Qemo
- Department of Biological Sciences, University of Windsor, Windsor, ON, Canada
| | - Lisa A Porter
- Department of Biological Sciences, University of Windsor, Windsor, ON, Canada.
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28
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Rahimi Ghiasi M, Rahimi E, Amirkhani Z, Salehi R. Leucine-rich Repeat-containing G-protein Coupled Receptor 5 Gene Overexpression of the Rat Small Intestinal Progenitor Cells in Response to Orally Administered Grape Exosome-like Nanovesicles. Adv Biomed Res 2018; 7:125. [PMID: 30211138 PMCID: PMC6124213 DOI: 10.4103/abr.abr_114_18] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Background: Grape exosome-like nanovesicles (GELNs) have the advantage of inherent biocompatibility and biodegradability, the potential to be used as oral delivery vehicles. The objective of this research was to evaluate the efficiency of Syrah GELN purification and their effects on the intestinal stem cells when orally administrated to the rats. Materials and Methods: In this experimental study, Syrah GELN isolated by differential centrifugation and sucrose gradient ultracentrifugation method, then the concentration of protein, size, and zeta potential were measured as well as nanoparticles morphology. The stability of nanoparticles was investigated in the solution that mimicked the condition encountered in the stomach and intestine. To demonstrate transfection efficiency of intestinal stem cells, real-time PCR was carried out using rat leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5)-specific primers on cDNA derived from total RNA extracted from the upper part of the small intestine of GELN-treated rats and their controls. Results: The mean size, zeta potential, and concentration of nanoparticles were 205.1 nm, −12.5 mV, and 250 μg/ml, respectively. The result of stability test demonstrated that Syrah GELN were resistant to the harsh environment of the stomach. Lgr5 gene expression was increased by tenfold in GELN-treated rats compared with the controls. Conclusions: As intestinal stem cells are poorly accessible by common exogenous agents in vivo, oral delivery of GELNs provides a new approach to modulate the stem cell microenvironment for intestinal remodeling. This novel and effective method would help to overcome conditions such as inflammatory bowel disease, colorectal cancer, and applicable in regenerative medicine.
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Affiliation(s)
- Moosa Rahimi Ghiasi
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Elnaz Rahimi
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Zohreh Amirkhani
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Rasoul Salehi
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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29
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Mahdipour-Shirayeh A, Shahriyari L. Modeling Cell Dynamics in Colon and Intestinal Crypts: The Significance of Central Stem Cells in Tumorigenesis. Bull Math Biol 2018; 80:2273-2305. [PMID: 29978308 DOI: 10.1007/s11538-018-0457-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 06/18/2018] [Indexed: 01/14/2023]
Abstract
Colon and intestinal crypts have been widely chosen to study cell dynamics because of their fairly simple structures. In the colon and intestinal crypts, stem cells (SCs) are located at very bottom of the crypt, fully differentiated cells (FDs) are located in the top of the crypt, and transit-amplifying cells (TAs) are in the middle of the crypt between FDs and SCs. Recently, it has been discovered that there are two types of stem cells in the intestinal crypts: central stem cells (CeSCs) and border stem cells. To investigate dynamics of mutants in colon and intestinal crypts, we develop a four-compartmental stochastic model, which includes two SC compartments, and TAs and FDs compartments. We calculate the probability of the progeny of marked or mutant cells located at each of these compartments taking over the entire crypt or being washed out from the crypt. We found that the progeny of CeSCs will take over the entire crypt with a probability close to one. Interestingly, the progeny of advantageous mutant TAs and FDs will be washed out faster than disadvantageous mutants. Saliently, the model predicts that the time that the progeny of wild-type central stem cells will take over the mouse intestinal crypt is around 60 days, which is in perfect agreement with an experimental observation.
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Affiliation(s)
- Ali Mahdipour-Shirayeh
- Biomedical Research Group, Applied Mathematics Department, University of Waterloo, Waterloo, ON, Canada. .,Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
| | - Leili Shahriyari
- Mathematical Biosciences Institute, The Ohio State University, Columbus, OH, USA
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30
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Nicholson AM, Olpe C, Hoyle A, Thorsen AS, Rus T, Colombé M, Brunton-Sim R, Kemp R, Marks K, Quirke P, Malhotra S, Ten Hoopen R, Ibrahim A, Lindskog C, Myers MB, Parsons B, Tavaré S, Wilkinson M, Morrissey E, Winton DJ. Fixation and Spread of Somatic Mutations in Adult Human Colonic Epithelium. Cell Stem Cell 2018; 22:909-918.e8. [PMID: 29779891 PMCID: PMC5989058 DOI: 10.1016/j.stem.2018.04.020] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Revised: 02/16/2018] [Accepted: 04/23/2018] [Indexed: 12/21/2022]
Abstract
We investigated the means and timing by which mutations become fixed in the human colonic epithelium by visualizing somatic clones and mathematical inference. Fixation requires two sequential steps. First, one of approximately seven active stem cells residing within each colonic crypt has to be mutated. Second, the mutated stem cell has to replace neighbors to populate the entire crypt in a process that takes several years. Subsequent clonal expansion due to crypt fission is infrequent for neutral mutations (around 0.7% of all crypts undergo fission in a single year). Pro-oncogenic mutations subvert both stem cell replacement to accelerate fixation and clonal expansion by crypt fission to achieve high mutant allele frequencies with age. The benchmarking of these behaviors allows the advantage associated with different gene-specific mutations to be compared irrespective of the cellular mechanisms by which they are conferred.
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Affiliation(s)
- Anna M Nicholson
- Cancer Research-UK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
| | - Cora Olpe
- Cancer Research-UK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK; Wellcome Trust-Medical Research Council, Cambridge Stem Cell Institute, Cambridge, UK
| | - Alice Hoyle
- Cancer Research-UK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
| | - Ann-Sofie Thorsen
- Cancer Research-UK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
| | - Teja Rus
- Cancer Research-UK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
| | - Mathilde Colombé
- Cancer Research-UK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
| | | | - Richard Kemp
- Cancer Research-UK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
| | - Kate Marks
- Pathology and Tumour Biology, Level 4, Wellcome Trust Brenner Building, St. James University Hospital, Beckett Street, Leeds LS9 7TF, UK
| | - Phil Quirke
- Pathology and Tumour Biology, Level 4, Wellcome Trust Brenner Building, St. James University Hospital, Beckett Street, Leeds LS9 7TF, UK
| | | | | | - Ashraf Ibrahim
- Department of Histopathology, Box 235, CUHFT, Cambridge, UK
| | - Cecilia Lindskog
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala 751 85, Sweden
| | - Meagan B Myers
- Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, US Food and Drug Administration, HFT-120, 3900 NCTR Road, Jefferson, AR 72079, USA
| | - Barbara Parsons
- Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, US Food and Drug Administration, HFT-120, 3900 NCTR Road, Jefferson, AR 72079, USA
| | - Simon Tavaré
- Cancer Research-UK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
| | - Mark Wilkinson
- Norwich Research Park BioRepository, James Watson Road, Norwich NR4 7UQ, UK
| | - Edward Morrissey
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK.
| | - Douglas J Winton
- Cancer Research-UK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
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31
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Stamp C, Zupanic A, Sachdeva A, Stoll EA, Shanley DP, Mathers JC, Kirkwood TBL, Heer R, Simons BD, Turnbull DM, Greaves LC. Predominant Asymmetrical Stem Cell Fate Outcome Limits the Rate of Niche Succession in Human Colonic Crypts. EBioMedicine 2018; 31:166-173. [PMID: 29748033 PMCID: PMC6013780 DOI: 10.1016/j.ebiom.2018.04.017] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Revised: 03/20/2018] [Accepted: 04/19/2018] [Indexed: 01/10/2023] Open
Abstract
Stem cell (SC) dynamics within the human colorectal crypt SC niche remain poorly understood, with previous studies proposing divergent hypotheses on the predominant mode of SC self-renewal and the rate of SC replacement. Here we use age-related mitochondrial oxidative phosphorylation (OXPHOS) defects to trace clonal lineages within human colorectal crypts across the adult life-course. By resolving the frequency and size distribution of OXPHOS-deficient clones, quantitative analysis shows that, in common with mouse, long-term maintenance of the colonic epithelial crypt relies on stochastic SC loss and replacement mediated by competition for limited niche access. We find that the colonic crypt is maintained by ~5 effective SCs. However, with a SC loss/replacement rate estimated to be slower than once per year, our results indicate that the vast majority of individual SC divisions result in asymmetric fate outcome. These findings provide a quantitative platform to detect and study deviations from human colorectal crypt SC niche homeostasis during the process of colorectal carcinogenesis.
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Affiliation(s)
- Craig Stamp
- LLHW Centre for Ageing and Vitality, Newcastle University Institute for Ageing, The Medical School, Newcastle upon Tyne NE2 4HH, UK; Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Anze Zupanic
- Swiss Federal Institute of Aquatic Science and Technology, Department of Environmental Toxicology, Dübendorf, Switzerland
| | - Ashwin Sachdeva
- Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE2 4HH, UK; Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4AD, UK
| | - Elizabeth A Stoll
- Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Daryl P Shanley
- Institute of Cell and Molecular Biosciences, Newcastle University Institute for Ageing, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne NE4 5PL, UK
| | - John C Mathers
- LLHW Centre for Ageing and Vitality, Newcastle University Institute for Ageing, The Medical School, Newcastle upon Tyne NE2 4HH, UK; Human Nutrition Research Centre, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE4 5PL, UK
| | - Thomas B L Kirkwood
- Institute of Cell and Molecular Biosciences, Newcastle University Institute for Ageing, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne NE4 5PL, UK
| | - Rakesh Heer
- Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4AD, UK
| | - Benjamin D Simons
- Cavendish Laboratory, Department of Physics, University of Cambridge, J.J. Thomson Avenue, Cambridge CB3 0HE, UK; Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK; Wellcome Trust/Medical Research Council SC Institute, Cambridge CB2 1QR, UK
| | - Doug M Turnbull
- LLHW Centre for Ageing and Vitality, Newcastle University Institute for Ageing, The Medical School, Newcastle upon Tyne NE2 4HH, UK; Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Laura C Greaves
- LLHW Centre for Ageing and Vitality, Newcastle University Institute for Ageing, The Medical School, Newcastle upon Tyne NE2 4HH, UK; Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
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32
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Li S, Han Z, Zhao N, Zhu B, Zhang Q, Yang X, Sheng D, Hou J, Guo S, Wei L, Zhang L. Inhibition of DNMT suppresses the stemness of colorectal cancer cells through down-regulating Wnt signaling pathway. Cell Signal 2018; 47:79-87. [PMID: 29601907 DOI: 10.1016/j.cellsig.2018.03.014] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Revised: 03/19/2018] [Accepted: 03/25/2018] [Indexed: 12/19/2022]
Abstract
Cancer stem cell (CSC) theory reveals a new insight into the understanding of tumorigenesis and metastasis. Recently, DNA methylation is suggested to be a potential epigenetic mechanism for maintenance of CSCs. What's more, studies have shown that DNA methyltransferase (DNMT) is essential for CSCs and deletion of DNMT can reduce tumorigenesis by limiting CSC pool. Therefore, targeting the epigenetic modifiers especially DNA methylation offers an optional strategy for treating human cancers. In the present study we found that DNMT inhibitor 5-Aza-2'-deoxycytidine (5-AzaDC) markedly reduced colorectal CSC abundance in vitro and suppressed liver metastatic tumor growth in vivo. And 5-AzaDC inhibited the expression of active β-catenin and down-regulated the Wnt signaling pathway. The Wnt inhibitors were frequently inactivated by promoter methylation in colorectal cancer; however analysis of TCGA data base showed that only the expression of SFRP1 was significantly reduced in tumors compared to normal tissues. In addition, restoring of SFRP1 expression inhibited the stem cell-like potential of colorectal cancer cells. Our results indicated that inhibition of DNMT blocked the self-renewal of colorectal CSCs and SFRP1 was essential for the maintenance of colorectal CSCs.
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Affiliation(s)
- Shanxin Li
- Department of Pharmacy, Changhai Hospital, The Second Military Medical University, Shanghai, China
| | - Zhipeng Han
- Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China
| | - Naping Zhao
- Department of Pharmacy, Changhai Hospital, The Second Military Medical University, Shanghai, China
| | - Bing Zhu
- Department of Pharmacy, Changhai Hospital, The Second Military Medical University, Shanghai, China
| | - Qianwen Zhang
- Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, China
| | - Xue Yang
- Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China
| | - Dandan Sheng
- Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China
| | - Jing Hou
- Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shiwei Guo
- Third Department of General Surgery, Changhai Hospital, The Second Military Medical University, Shanghai, China
| | - Lixin Wei
- Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.
| | - Li Zhang
- Department of Pharmacy, Changhai Hospital, The Second Military Medical University, Shanghai, China.
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33
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Fendrik AJ, Romanelli L, Rotondo E. Neutral dynamics and cell renewal of colonic crypts in homeostatic regime. Phys Biol 2018; 15:036003. [PMID: 29381141 DOI: 10.1088/1478-3975/aaab9f] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
The self renewal process in colonic crypts is the object of several studies. We present here a new compartment model with the following characteristics: (a) we distinguish different classes of cells: stem cells, six generations of transit amplifying cells and the differentiated cells; (b) in order to take into account the monoclonal character of crypts in homeostatic regimes we include symmetric divisions of the stem cells. We first consider the dynamic differential equations that describe the evolution of the mean values of the populations, but the small observed value of the total number of cells involved plus the huge dispersion of experimental data found in the literature leads us to study the stochastic discrete process. This analysis allows us to study fluctuations, the neutral drift that leads to monoclonality, and the effects of the fixation of mutant clones.
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Affiliation(s)
- A J Fendrik
- Instituto de Ciencias, Universidad Nacional de General Sarmiento-J.M.Gutierrez 1150, (1613) Los Polvorines, Buenos Aires, Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas- Buenos Aires, Argentina. Author to whom any correspondence should be addressed
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34
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Cardelli M. The epigenetic alterations of endogenous retroelements in aging. Mech Ageing Dev 2018; 174:30-46. [PMID: 29458070 DOI: 10.1016/j.mad.2018.02.002] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Revised: 02/05/2018] [Accepted: 02/08/2018] [Indexed: 02/06/2023]
Abstract
Endogenous retroelements, transposons that mobilize through RNA intermediates, include some of the most abundant repetitive sequences of the human genome, such as Alu and LINE-1 sequences, and human endogenous retroviruses. Recent discoveries demonstrate that these mobile genetic elements not only act as intragenomic parasites, but also exert regulatory roles in living cells. The risk of genomic instability represented by endogenous retroelements is normally counteracted by a series of epigenetic control mechanisms which include, among the most important, CpG DNA methylation. Indeed, most of the genomic CpG sites subjected to DNA methylation in the nuclear DNA are carried by these repetitive elements. As other parts of the genome, endogenous retroelements and other transposable elements are subjected to deep epigenetic alterations during aging, repeatedly observed in the context of organismal and cellular senescence, in human and other species. This review summarizes the current status of knowledge about the epigenetic alterations occurring in this large, non-genic portion of the genome in aging and age-related conditions, with a focus on the causes and the possible functional consequences of these alterations.
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Affiliation(s)
- Maurizio Cardelli
- Advanced Technology Center for Aging Research, Scientific Technological Area, Italian National Research Center on Aging (INRCA), via Birarelli 8, 60121 Ancona, Italy.
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35
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Blum W, Henzi T, Schwaller B, Pecze L. Biological noise and positional effects influence cell stemness. J Biol Chem 2018; 293:5247-5258. [PMID: 29440274 DOI: 10.1074/jbc.ra117.001643] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2017] [Revised: 02/12/2018] [Indexed: 01/01/2023] Open
Abstract
Biological (or cellular) noise is the random quantitative variability of proteins and other molecules in individual, genetically identical cells. As the result of biological noise in the levels of some transcription factors that determine a cell's differentiation status, differentiated cells may dedifferentiate to a stem cell state given a sufficiently long time period. Here, to provide direct evidence supporting this hypothesis, we used a live-cell monitoring system based on enhanced green fluorescent protein (eGFP) expression to continuously assess the "stemness" of individual human and murine malignant mesothelioma cells over a period of up to 3 months. Re-expression of the transcription factors, the top hierarchical stemness markers Sox2 (SRY-box 2) and Oct4 (octamer-binding transcription factor), monitored as cell eGFP expression was observed in a subpopulation of differentiated eGFP(-) malignant mesothelioma cells. However, we found that this transition was extremely rare. Of note, when it did occur, neighboring cells that were not direct descendants of a newly emerged eGFP(+) stem cell were more likely than non-neighboring cells to also become an eGFP(+) stem cell. This observation suggested a positional effect and led to a clustered "mosaic" reappearance of eGFP(+) stem cells. Moreover, stem cells reappeared even in cell cultures derived from one single differentiated eGFP(-) cell. On the basis of our experimental in vitro and in vivo findings, we developed a tumor growth model to predict the clustered localization of cancer stem cells within a tumor mass.
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Affiliation(s)
- Walter Blum
- From the Unit of Anatomy, Section of Medicine, University of Fribourg, 1700 Fribourg, Switzerland
| | - Thomas Henzi
- From the Unit of Anatomy, Section of Medicine, University of Fribourg, 1700 Fribourg, Switzerland
| | - Beat Schwaller
- From the Unit of Anatomy, Section of Medicine, University of Fribourg, 1700 Fribourg, Switzerland
| | - László Pecze
- From the Unit of Anatomy, Section of Medicine, University of Fribourg, 1700 Fribourg, Switzerland
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36
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Assenov Y, Brocks D, Gerhäuser C. Intratumor heterogeneity in epigenetic patterns. Semin Cancer Biol 2018; 51:12-21. [PMID: 29366906 DOI: 10.1016/j.semcancer.2018.01.010] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Revised: 11/24/2017] [Accepted: 01/17/2018] [Indexed: 02/08/2023]
Abstract
Analogous to life on earth, tumor cells evolve through space and time and adapt to different micro-environmental conditions. As a result, tumors are composed of millions of genetically diversified cells at the time of diagnosis. Profiling these variants contributes to understanding tumors' clonal origins and might help to better understand response to therapy. However, even genetically homogenous cell populations show remarkable diversity in their response to different environmental stimuli, suggesting that genetic heterogeneity does not explain the full spectrum of tumor plasticity. Understanding epigenetic diversity across cancer cells provides important additional information about the functional state of subclones and therefore allows better understanding of tumor evolution and resistance to current therapies.
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Affiliation(s)
- Yassen Assenov
- Epigenomics and Cancer Risk Factors, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - David Brocks
- Epigenomics and Cancer Risk Factors, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - Clarissa Gerhäuser
- Epigenomics and Cancer Risk Factors, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
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Abstract
Where does cancer come from? Although the cell-of-origin is difficult to pinpoint, cancer clones harbor information about their clonal ancestries. In an effort to find cells before they evolve into a life-threatening cancer, physicians currently diagnose premalignant diseases at frequencies that substantially exceed those of clinical cancers. Cancer risk prediction relies on our ability to distinguish between which premalignant features will lead to cancer mortality and which are characteristic of inconsequential disease. Here, we review the evolution of cancer from premalignant disease, and discuss the concept that even phenotypically normal cell progenies inherently gain more malignant potential with age. We describe the hurdles of prognosticating cancer risk in premalignant disease by making reference to the underlying continuous and multivariate natures of genotypes and phenotypes and the particular challenge inherent in defining a cell lineage as "cancerized."
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Affiliation(s)
- Kit Curtius
- Centre for Tumor Biology, Barts Cancer Institute, EC1M 6BQ London, United Kingdom
| | - Nicholas A Wright
- Centre for Tumor Biology, Barts Cancer Institute, EC1M 6BQ London, United Kingdom
| | - Trevor A Graham
- Centre for Tumor Biology, Barts Cancer Institute, EC1M 6BQ London, United Kingdom
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38
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Yang J, Axelrod DE, Komarova NL. Determining the control networks regulating stem cell lineages in colonic crypts. J Theor Biol 2017; 429:190-203. [PMID: 28669884 PMCID: PMC5689466 DOI: 10.1016/j.jtbi.2017.06.033] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Revised: 05/18/2017] [Accepted: 06/25/2017] [Indexed: 12/27/2022]
Abstract
The question of stem cell control is at the center of our understanding of tissue functioning, both in healthy and cancerous conditions. It is well accepted that cellular fate decisions (such as divisions, differentiation, apoptosis) are orchestrated by a network of regulatory signals emitted by different cell populations in the lineage and the surrounding tissue. The exact regulatory network that governs stem cell lineages in a given tissue is usually unknown. Here we propose an algorithm to identify a set of candidate control networks that are compatible with (a) measured means and variances of cell populations in different compartments, (b) qualitative information on cell population dynamics, such as the existence of local controls and oscillatory reaction of the system to population size perturbations, and (c) statistics of correlations between cell numbers in different compartments. Using the example of human colon crypts, where lineages are comprised of stem cells, transit amplifying cells, and differentiated cells, we start with a theoretically known set of 32 smallest control networks compatible with tissue stability. Utilizing near-equilibrium stochastic calculus of stem cells developed earlier, we apply a series of tests, where we compare the networks' expected behavior with the observations. This allows us to exclude most of the networks, until only three, very similar, candidate networks remain, which are most compatible with the measurements. This work demonstrates how theoretical analysis of control networks combined with only static biological data can shed light onto the inner workings of stem cell lineages, in the absence of direct experimental assessment of regulatory signaling mechanisms. The resulting candidate networks are dominated by negative control loops and possess the following properties: (1) stem cell division decisions are negatively controlled by the stem cell population, (2) stem cell differentiation decisions are negatively controlled by the transit amplifying cell population.
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Affiliation(s)
- Jienian Yang
- Department of Mathematics, University of California, Irvine, Irvine, CA 92697 USA
| | - David E Axelrod
- Department of Genetics and Cancer Institute of New Jersey, Rutgers University, Piscataway, NJ 08854-8082, USA
| | - Natalia L Komarova
- Department of Ecology and Evolutionary Biology, University of California, Irvine, Irvine, CA 92697, USA.
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Ma H, Brosens LAA, Elias SG, Morsink FHM, Nijman IJ, Hylind LM, Montgomery EA, Offerhaus GJA, Giardiello FM, de Leng WWJ. Longitudinal analysis of colon crypt stem cell dynamics in sulindac treated Familial Adenomatous Polyposis patients. Sci Rep 2017; 7:11972. [PMID: 28931879 PMCID: PMC5607292 DOI: 10.1038/s41598-017-11865-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Accepted: 08/24/2017] [Indexed: 02/06/2023] Open
Abstract
The non-steroidal anti-inflammatory drug sulindac decreases size and number of adenomas after 4-6 months of treatment for familial adenomatous polyposis (FAP) patients. However, the underlying mechanism remains unknown. As stem cells are thought to be the tumor precursor cells, visualizing their behavior is crucial for monitoring tumor progression. Increased tag diversity in inactive genes is indicative of a protracted clonal evolution and consequently, increased risk for tumor formation. Therefore, the effect of sulindac on stem cell dynamics was studied. Normal appearing single crypts were laser microdissected in placebo- and sulindac- treated FAP patient tissue after which the methylation patterns were visualized by Next Generation Sequencing. A significant difference in tag diversity over time was found in the sulindac group compared to the placebo group (*p = 0.018), indicative of a shortened clonal evolution treated sulindac. The rate of change in tag diversity over time was correlated with polyp number change over time. No significant difference over time was observed in the percent methylation when comparing placebo vs sulindac. In conclusion, daily sulindac administration in FAP patients significantly altered colorectal stem cell dynamics, which might explain the chemopreventive action of this drug indicating that tag diversity may be used as a predictive biomarker.
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Affiliation(s)
- Huiying Ma
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Lodewijk A A Brosens
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Sjoerd G Elias
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Folkert H M Morsink
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Isaac J Nijman
- Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Linda M Hylind
- Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Elizabeth A Montgomery
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - G Johan A Offerhaus
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Francis M Giardiello
- Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Wendy W J de Leng
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
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40
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Stability of Control Networks in Autonomous Homeostatic Regulation of Stem Cell Lineages. Bull Math Biol 2017; 80:1345-1365. [PMID: 28508298 DOI: 10.1007/s11538-017-0283-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2016] [Accepted: 04/07/2017] [Indexed: 01/02/2023]
Abstract
Design principles of biological networks have been studied extensively in the context of protein-protein interaction networks, metabolic networks, and regulatory (transcriptional) networks. Here we consider regulation networks that occur on larger scales, namely the cell-to-cell signaling networks that connect groups of cells in multicellular organisms. These are the feedback loops that orchestrate the complex dynamics of cell fate decisions and are necessary for the maintenance of homeostasis in stem cell lineages. We focus on "minimal" networks that are those that have the smallest possible numbers of controls. For such minimal networks, the number of controls must be equal to the number of compartments, and the reducibility/irreducibility of the network (whether or not it can be split into smaller independent sub-networks) is defined by a matrix comprised of the cell number increments induced by each of the controlled processes in each of the compartments. Using the formalism of digraphs, we show that in two-compartment lineages, reducible systems must contain two 1-cycles, and irreducible systems one 1-cycle and one 2-cycle; stability follows from the signs of the controls and does not require magnitude restrictions. In three-compartment systems, irreducible digraphs have a tree structure or have one 3-cycle and at least two more shorter cycles, at least one of which is a 1-cycle. With further work and proper biological validation, our results may serve as a first step toward an understanding of ways in which these networks become dysregulated in cancer.
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41
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Xiao X, Chang H, Li M. Molecular mechanisms underlying noncoding risk variations in psychiatric genetic studies. Mol Psychiatry 2017; 22:497-511. [PMID: 28044063 PMCID: PMC5378805 DOI: 10.1038/mp.2016.241] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Revised: 11/08/2016] [Accepted: 11/14/2016] [Indexed: 12/18/2022]
Abstract
Recent large-scale genetic approaches such as genome-wide association studies have allowed the identification of common genetic variations that contribute to risk architectures of psychiatric disorders. However, most of these susceptibility variants are located in noncoding genomic regions that usually span multiple genes. As a result, pinpointing the precise variant(s) and biological mechanisms accounting for the risk remains challenging. By reviewing recent progresses in genetics, functional genomics and neurobiology of psychiatric disorders, as well as gene expression analyses of brain tissues, here we propose a roadmap to characterize the roles of noncoding risk loci in the pathogenesis of psychiatric illnesses (that is, identifying the underlying molecular mechanisms explaining the genetic risk conferred by those genomic loci, and recognizing putative functional causative variants). This roadmap involves integration of transcriptomic data, epidemiological and bioinformatic methods, as well as in vitro and in vivo experimental approaches. These tools will promote the translation of genetic discoveries to physiological mechanisms, and ultimately guide the development of preventive, therapeutic and prognostic measures for psychiatric disorders.
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Affiliation(s)
- X Xiao
- Key Laboratory of Animal Models and Human Disease Mechanisms of The Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China
| | - H Chang
- Key Laboratory of Animal Models and Human Disease Mechanisms of The Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China
| | - M Li
- Key Laboratory of Animal Models and Human Disease Mechanisms of The Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China
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42
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Gagliano SA. It's All in the Brain: A Review of Available Functional Genomic Annotations. Biol Psychiatry 2017; 81:478-483. [PMID: 27788914 DOI: 10.1016/j.biopsych.2016.08.011] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Revised: 08/02/2016] [Accepted: 08/04/2016] [Indexed: 10/21/2022]
Abstract
What makes the molecular study of psychiatric and other neurological conditions particularly challenging compared with other complex traits is the difficulty of accessing the relevant tissue. The Encyclopedia of DNA Elements (ENCODE) project was one of the earliest producers of brain-derived epigenetic functional genomic data, albeit initially from only two cancerous brain cell lines for a limited number of epigenetic marks. It has only been in very recent years that such data from human brain tissue have been made available from various sources. Yet, these data are scattered throughout the literature with no central organization. This review summarizes the availability and accessibility of brain epigenetic and functional genomic data as a single resource to allow investigators to easily access available brain annotations and thus incorporate this wealth of information into their research to make important advances in the field of neuroscience.
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Affiliation(s)
- Sarah A Gagliano
- Centre for Addiction and Mental Health, Campbell Family Mental Health Research Institute, Toronto, Canada; Department of Medical & Molecular Genetics, Guy's Hospital, King's College London, London, United Kingdom.
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43
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Pérez S, Taléns-Visconti R, Rius-Pérez S, Finamor I, Sastre J. Redox signaling in the gastrointestinal tract. Free Radic Biol Med 2017; 104:75-103. [PMID: 28062361 DOI: 10.1016/j.freeradbiomed.2016.12.048] [Citation(s) in RCA: 195] [Impact Index Per Article: 24.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2016] [Revised: 12/20/2016] [Accepted: 12/31/2016] [Indexed: 12/16/2022]
Abstract
Redox signaling regulates physiological self-renewal, proliferation, migration and differentiation in gastrointestinal epithelium by modulating Wnt/β-catenin and Notch signaling pathways mainly through NADPH oxidases (NOXs). In the intestine, intracellular and extracellular thiol redox status modulates the proliferative potential of epithelial cells. Furthermore, commensal bacteria contribute to intestine epithelial homeostasis through NOX1- and dual oxidase 2-derived reactive oxygen species (ROS). The loss of redox homeostasis is involved in the pathogenesis and development of a wide diversity of gastrointestinal disorders, such as Barrett's esophagus, esophageal adenocarcinoma, peptic ulcer, gastric cancer, ischemic intestinal injury, celiac disease, inflammatory bowel disease and colorectal cancer. The overproduction of superoxide anion together with inactivation of superoxide dismutase are involved in the pathogenesis of Barrett's esophagus and its transformation to adenocarcinoma. In Helicobacter pylori-induced peptic ulcer, oxidative stress derived from the leukocyte infiltrate and NOX1 aggravates mucosal damage, especially in HspB+ strains that downregulate Nrf2. In celiac disease, oxidative stress mediates most of the cytotoxic effects induced by gluten peptides and increases transglutaminase levels, whereas nitrosative stress contributes to the impairment of tight junctions. Progression of inflammatory bowel disease relies on the balance between pro-inflammatory redox-sensitive pathways, such as NLRP3 inflammasome and NF-κB, and the adaptive up-regulation of Mn superoxide dismutase and glutathione peroxidase 2. In colorectal cancer, redox signaling exhibits two Janus faces: On the one hand, NOX1 up-regulation and derived hydrogen peroxide enhance Wnt/β-catenin and Notch proliferating pathways; on the other hand, ROS may disrupt tumor progression through different pro-apoptotic mechanisms. In conclusion, redox signaling plays a critical role in the physiology and pathophysiology of gastrointestinal tract.
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Affiliation(s)
- Salvador Pérez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Burjasot, 46100 Valencia, Spain
| | - Raquel Taléns-Visconti
- Department of Pharmacy and Pharmaceutical Technology and Parasitology, Faculty of Pharmacy, University of Valencia, Burjasot, 46100 Valencia, Spain
| | - Sergio Rius-Pérez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Burjasot, 46100 Valencia, Spain
| | - Isabela Finamor
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Burjasot, 46100 Valencia, Spain
| | - Juan Sastre
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Burjasot, 46100 Valencia, Spain.
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44
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Li Y, Tollefsbol TO. Age-related epigenetic drift and phenotypic plasticity loss: implications in prevention of age-related human diseases. Epigenomics 2016; 8:1637-1651. [PMID: 27882781 PMCID: PMC5618938 DOI: 10.2217/epi-2016-0078] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Aging is considered as one of the most important developmental processes in organisms and is closely associated with global deteriorations of epigenetic markers such as aberrant methylomic patterns. This altered epigenomic state, referred to 'epigenetic drift', reflects deficient maintenance of epigenetic marks and contributes to impaired cellular and molecular functions in aged cells. Epigenetic drift-induced abnormal changes during aging are scantily repaired by epigenetic modulators. This inflexibility in the aged epigenome may lead to an age-related decline in phenotypic plasticity at the cellular and molecular levels due to epigenetic drift. This perspective aims to provide novel concepts for understanding epigenetic effects on the aging process and to provide insights into epigenetic prevention and therapeutic strategies for age-related human disease.
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Affiliation(s)
- Yuanyuan Li
- Department of Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.,Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.,Nutrition Obesity Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Trygve O Tollefsbol
- Department of Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.,Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.,Nutrition Obesity Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.,Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.,Comprehensive Center for Healthy Aging, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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45
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Yang Z, Wong A, Kuh D, Paul DS, Rakyan VK, Leslie RD, Zheng SC, Widschwendter M, Beck S, Teschendorff AE. Correlation of an epigenetic mitotic clock with cancer risk. Genome Biol 2016; 17:205. [PMID: 27716309 PMCID: PMC5046977 DOI: 10.1186/s13059-016-1064-3] [Citation(s) in RCA: 199] [Impact Index Per Article: 22.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Background Variation in cancer risk among somatic tissues has been attributed to variations in the underlying rate of stem cell division. For a given tissue type, variable cancer risk between individuals is thought to be influenced by extrinsic factors which modulate this rate of stem cell division. To date, no molecular mitotic clock has been developed to approximate the number of stem cell divisions in a tissue of an individual and which is correlated with cancer risk. Results Here, we integrate mathematical modeling with prior biological knowledge to construct a DNA methylation-based age-correlative model which approximates a mitotic clock in both normal and cancer tissue. By focusing on promoter CpG sites that localize to Polycomb group target genes that are unmethylated in 11 different fetal tissue types, we show that increases in DNA methylation at these sites defines a tick rate which correlates with the estimated rate of stem cell division in normal tissues. Using matched DNA methylation and RNA-seq data, we further show that it correlates with an expression-based mitotic index in cancer tissue. We demonstrate that this mitotic-like clock is universally accelerated in cancer, including pre-cancerous lesions, and that it is also accelerated in normal epithelial cells exposed to a major carcinogen. Conclusions Unlike other epigenetic and mutational clocks or the telomere clock, the epigenetic clock proposed here provides a concrete example of a mitotic-like clock which is universally accelerated in cancer and precancerous lesions. Electronic supplementary material The online version of this article (doi:10.1186/s13059-016-1064-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Zhen Yang
- CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, 320 Yue Yang Road, Shanghai, 200031, China
| | - Andrew Wong
- MRC Unit for Lifelong Health and Ageing at University College London, London, UK
| | - Diana Kuh
- MRC Unit for Lifelong Health and Ageing at University College London, London, UK
| | - Dirk S Paul
- Medical Genomics, UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6BT, UK
| | - Vardhman K Rakyan
- The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, E1 2AT, UK
| | - R David Leslie
- The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, E1 2AT, UK
| | - Shijie C Zheng
- CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, 320 Yue Yang Road, Shanghai, 200031, China
| | - Martin Widschwendter
- Department of Women's Cancer, University College London, 74 Huntley Street, London, WC1E 6AU, UK
| | - Stephan Beck
- Medical Genomics, UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6BT, UK
| | - Andrew E Teschendorff
- CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, 320 Yue Yang Road, Shanghai, 200031, China. .,Department of Women's Cancer, University College London, 74 Huntley Street, London, WC1E 6AU, UK. .,Statistical Cancer Genomics, Paul O'Gorman Building, UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6BT, UK.
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46
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Niwa O, Barcellos-Hoff MH, Globus RK, Harrison JD, Hendry JH, Jacob P, Martin MT, Seed TM, Shay JW, Story MD, Suzuki K, Yamashita S. ICRP Publication 131: Stem Cell Biology with Respect to Carcinogenesis Aspects of Radiological Protection. Ann ICRP 2016; 44:7-357. [PMID: 26637346 DOI: 10.1177/0146645315595585] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
This report provides a review of stem cells/progenitor cells and their responses to ionising radiation in relation to issues relevant to stochastic effects of radiation that form a major part of the International Commission on Radiological Protection's system of radiological protection. Current information on stem cell characteristics, maintenance and renewal, evolution with age, location in stem cell 'niches', and radiosensitivity to acute and protracted exposures is presented in a series of substantial reviews as annexes concerning haematopoietic tissue, mammary gland, thyroid, digestive tract, lung, skin, and bone. This foundation of knowledge of stem cells is used in the main text of the report to provide a biological insight into issues such as the linear-no-threshold (LNT) model, cancer risk among tissues, dose-rate effects, and changes in the risk of radiation carcinogenesis by age at exposure and attained age. Knowledge of the biology and associated radiation biology of stem cells and progenitor cells is more developed in tissues that renew fairly rapidly, such as haematopoietic tissue, intestinal mucosa, and epidermis, although all the tissues considered here possess stem cell populations. Important features of stem cell maintenance, renewal, and response are the microenvironmental signals operating in the niche residence, for which a well-defined spatial location has been identified in some tissues. The identity of the target cell for carcinogenesis continues to point to the more primitive stem cell population that is mostly quiescent, and hence able to accumulate the protracted sequence of mutations necessary to result in malignancy. In addition, there is some potential for daughter progenitor cells to be target cells in particular cases, such as in haematopoietic tissue and in skin. Several biological processes could contribute to protecting stem cells from mutation accumulation: (a) accurate DNA repair; (b) rapidly induced death of injured stem cells; (c) retention of the DNA parental template strand during divisions in some tissue systems, so that mutations are passed to the daughter differentiating cells and not retained in the parental cell; and (d) stem cell competition, whereby undamaged stem cells outcompete damaged stem cells for residence in the niche. DNA repair mainly occurs within a few days of irradiation, while stem cell competition requires weeks or many months depending on the tissue type. The aforementioned processes may contribute to the differences in carcinogenic radiation risk values between tissues, and may help to explain why a rapidly replicating tissue such as small intestine is less prone to such risk. The processes also provide a mechanistic insight relevant to the LNT model, and the relative and absolute risk models. The radiobiological knowledge also provides a scientific insight into discussions of the dose and dose-rate effectiveness factor currently used in radiological protection guidelines. In addition, the biological information contributes potential reasons for the age-dependent sensitivity to radiation carcinogenesis, including the effects of in-utero exposure.
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Shahriyari L, Komarova NL, Jilkine A. The role of cell location and spatial gradients in the evolutionary dynamics of colon and intestinal crypts. Biol Direct 2016; 11:42. [PMID: 27549762 PMCID: PMC4994304 DOI: 10.1186/s13062-016-0141-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2016] [Accepted: 07/15/2016] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Colon and intestinal crypts serve as an important model system for adult stem cell proliferation and differentiation. We develop a spatial stochastic model to study the rate of somatic evolution in a normal crypt, focusing on the production of two-hit mutants that inactivate a tumor suppressor gene. We investigate the effect of cell division pattern along the crypt on mutant production, assuming that the division rate of each cell depends on its location. RESULTS We find that higher probability of division at the bottom of the crypt, where the stem cells are located, leads to a higher rate of double-hit mutant production. The optimal case for delaying mutations occurs when most of the cell divisions happen at the top of the crypt. We further consider an optimization problem where the "evolutionary" penalty for double-hit mutant generation is complemented with a "functional" penalty that assures that fully differentiated cells at the top of the crypt cannot divide. CONCLUSION The trade-off between the two types of objectives leads to the selection of an intermediate division pattern, where the cells in the middle of the crypt divide with the highest rate. This matches the pattern of cell divisions obtained experimentally in murine crypts. REVIEWERS This article was reviewed by David Axelrod (nominated by an Editorial Board member, Marek Kimmel), Yang Kuang and Anna Marciniak-Czochra. For the full reviews, please go to the Reviewers' comments section.
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Affiliation(s)
- Leili Shahriyari
- Mathematical Biosciences Institute, The Ohio State University, 1735 Neil Ave, Columbus, 43210, USA
| | - Natalia L Komarova
- Department of Mathematics, University of California Irvine, 340 Rowland Hall, Irvine, 92697, USA.
| | - Alexandra Jilkine
- Department of Applied and Computational Mathematics and Statistics, University of Notre Dame, 153 Hurley Hall, Notre Dame, 46556, USA.
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48
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A hybrid agent-based model of the developing mammary terminal end bud. J Theor Biol 2016; 407:259-270. [PMID: 27475843 DOI: 10.1016/j.jtbi.2016.07.040] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Revised: 07/15/2016] [Accepted: 07/25/2016] [Indexed: 12/13/2022]
Abstract
Mammary gland ductal elongation is spearheaded by terminal end buds (TEBs), where populations of highly proliferative cells are maintained throughout post-pubertal organogenesis in virgin mice until the mammary fat pad is filled by a mature ductal tree. We have developed a hybrid multiscale agent-based model to study how cellular differentiation pathways, cellular proliferation capacity, and endocrine and paracrine signaling play a role during development of the mammary gland. A simplified cellular phenotypic hierarchy that includes stem, progenitor, and fully differentiated cells within the TEB was implemented. Model analysis finds that mammary gland development was highly sensitive to proliferation events within the TEB, with progenitors likely undergoing 2-3 proliferation cycles before transitioning to a non-proliferative phenotype, and this result is in agreement with our previous experimental work. Endocrine and paracrine signaling were found to provide reliable ductal elongation rate regulation, while variations in the probability a new daughter cell will be of a proliferative phenotype were seen to have minimal effects on ductal elongation rates. Moreover, the distribution of cellular phenotypes within the TEB was highly heterogeneous, demonstrating significant allowable plasticity in possible phenotypic distributions while maintaining biologically relevant growth behavior. Finally, simulation results indicate ductal elongation rates due to cellular proliferation within the TEB may have a greater sensitivity to upstream endocrine signaling than endothelial to stromal paracrine signaling within the TEB. This model provides a useful tool to gain quantitative insights into cellular population dynamics and the effects of endocrine and paracrine signaling within the pubertal terminal end bud.
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49
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Sun Z, Plikus MV, Komarova NL. Near Equilibrium Calculus of Stem Cells in Application to the Airway Epithelium Lineage. PLoS Comput Biol 2016; 12:e1004990. [PMID: 27427948 PMCID: PMC4948767 DOI: 10.1371/journal.pcbi.1004990] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Accepted: 05/18/2016] [Indexed: 01/16/2023] Open
Abstract
Homeostatic maintenance of tissues is orchestrated by well tuned networks of cellular signaling. Such networks regulate, in a stochastic manner, fates of all cells within the respective lineages. Processes such as symmetric and asymmetric divisions, differentiation, de-differentiation, and death have to be controlled in a dynamic fashion, such that the cell population is maintained at a stable equilibrium, has a sufficiently low level of stochastic variation, and is capable of responding efficiently to external damage. Cellular lineages in real tissues may consist of a number of different cell types, connected by hierarchical relationships, albeit not necessarily linear, and engaged in a number of different processes. Here we develop a general mathematical methodology for near equilibrium studies of arbitrarily complex hierarchical cell populations, under regulation by a control network. This methodology allows us to (1) determine stability properties of the network, (2) calculate the stochastic variance, and (3) predict how different control mechanisms affect stability and robustness of the system. We demonstrate the versatility of this tool by using the example of the airway epithelium lineage. Recent research shows that airway epithelium stem cells divide mostly asymmetrically, while the so-called secretory cells divide predominantly symmetrically. It further provides quantitative data on the recovery dynamics of the airway epithelium, which can include secretory cell de-differentiation. Using our new methodology, we demonstrate that while a number of regulatory networks can be compatible with the observed recovery behavior, the observed division patterns of cells are the most optimal from the viewpoint of homeostatic lineage stability and minimizing the variation of the cell population size. This not only explains the observed yet poorly understood features of airway tissue architecture, but also helps to deduce the information on the still largely hypothetical regulatory mechanisms governing tissue turnover, and lends insight into how different control loops influence the stability and variance properties of cell populations. Tissue stability is the basic property of healthy organs, and yet the mechanisms governing the stable, long-term maintenance of cell numbers in tissues are poorly understood. While more and more signaling pathways are being discovered, for the most part it remains unknown how they are being put together by different cell types into complex, nonlinear, hierarchical control networks that, on the one hand, reliably maintain constant cell numbers, and on the other hand, quickly adjust to oversee the robust response to tissue damage. Theoretical approaches can fill the gap by being able to reconstruct the underlying control network, based on the observations about the aspects of cellular dynamics. We argue that while many hypothetical networks may be capable of basic cell lineage maintenance, some are much more efficient from the viewpoint of variance minimization. Thus, we developed a new methodology that can test various control networks for stability, variance, and robustness. In the example of the airway epithelium that we highlight, it turns out that the evolutionary selected, actual architecture coincides with the mathematically optimal solution that minimizes the fluctuations of cell numbers at homeostasis.
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Affiliation(s)
- Zheng Sun
- Department of Mathematics, University of California, Irvine, Irvine, California, United States of America
| | - Maksim V. Plikus
- Department of Developmental and Cell Biology, Sue and Bill Gross Stem Cell Research Center and Center for Complex Biological Systems, University of California, Irvine, Irvine, California, United States of America
| | - Natalia L. Komarova
- Department of Mathematics, University of California, Irvine, Irvine, California, United States of America
- Department of Ecology and Evolutionary Biology, University of California, Irvine, Irvine, California, United States of America
- * E-mail:
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Packer JR, Maitland NJ. The molecular and cellular origin of human prostate cancer. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2016; 1863:1238-60. [DOI: 10.1016/j.bbamcr.2016.02.016] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/04/2015] [Revised: 02/17/2016] [Accepted: 02/22/2016] [Indexed: 01/01/2023]
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