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1
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Jiang Y, Liang Y, Zhao F, Lu Z, Wang S, Meng Y, Liu Z, Zhang J, Zhao Y. Rtf1 HMD domain facilitates global histone H2B monoubiquitination and regulates morphogenesis and virulence in the meningitis-causing pathogen Cryptococcus neoformans. eLife 2025; 13:RP99229. [PMID: 40353352 PMCID: PMC12068867 DOI: 10.7554/elife.99229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/14/2025] Open
Abstract
Rtf1 is generally considered to be a subunit of the Paf1 complex (Paf1C), which is a multifunctional protein complex involved in histone modification and RNA biosynthesis at multiple stages. Rtf1 is stably associated with the Paf1C in Saccharomyces cerevisiae, but not in other species including humans. Little is known about its function in human fungal pathogens. Here, we show that Rtf1 is required for facilitating H2B monoubiquitination (H2Bub1), and regulates fungal morphogenesis and pathogenicity in the meningitis-causing fungal pathogen Cryptococcus neoformans. Rtf1 is not tightly associated with the Paf1C, and its histone modification domain (HMD) is sufficient to promote H2Bub1 and the expression of genes related to fungal mating and filamentation. Moreover, Rtf1 HMD fully restores fungal morphogenesis and pathogenicity; however, it fails to restore defects of thermal tolerance and melanin production in the rtf1Δ strain background. The present study establishes a role for cryptococcal Rtf1 as a Paf1C-independent regulator in regulating fungal morphogenesis and pathogenicity, and highlights the function of HMD in facilitating global H2Bub1 in C. neoformans.
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Affiliation(s)
- Yixuan Jiang
- College of Veterinary Medicine, Henan Agricultural UniversityZhengzhouChina
| | - Ying Liang
- College of Veterinary Medicine, Henan Agricultural UniversityZhengzhouChina
| | - Fujie Zhao
- College of Veterinary Medicine, Henan Agricultural UniversityZhengzhouChina
| | - Zhenguo Lu
- College of Veterinary Medicine, Henan Agricultural UniversityZhengzhouChina
| | - Siyu Wang
- College of Veterinary Medicine, Henan Agricultural UniversityZhengzhouChina
| | - Yao Meng
- College of Veterinary Medicine, Henan Agricultural UniversityZhengzhouChina
| | - Zhanxiang Liu
- College of Veterinary Medicine, Henan Agricultural UniversityZhengzhouChina
| | - Jing Zhang
- College of Veterinary Medicine, Henan Agricultural UniversityZhengzhouChina
| | - Youbao Zhao
- College of Veterinary Medicine, Henan Agricultural UniversityZhengzhouChina
- Key Laboratory of Quality and Safety Control of Poultry Products, Ministry of Agriculture and Rural AffairsZhengzhouChina
- Henan Province Key Laboratory of Animal Food Pathogens SurveillanceZhengzhouChina
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2
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Poncha KF, Paparella AT, Young NL. Normalized and Directional Interplay Scoring for the Interrogation of Proteoform Data. J Proteome Res 2025; 24:1765-1777. [PMID: 40020221 DOI: 10.1021/acs.jproteome.4c00877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/05/2025]
Abstract
Histone proteoforms, often presenting multiple co-occurring post-translational modifications (PTMs), are central to chromatin regulation and gene expression. A proteoform is a specific form of a protein that includes variations arising from genetic changes, alternative RNA splicing, proteolytic processing, and PTMs. Genome-indexed histone proteoforms define the histone code, influencing cellular phenotype by dictating DNA interacting partners. Understanding the dynamics of histone proteoforms is essential for elucidating chromatin-based regulatory mechanisms. Advances in middle-down and top-down proteomics enable accurate identification and quantitation of thousands of proteoforms in a single run. However, the resulting data complexity presents significant challenges for analysis and visualization. Here, we introduce two new computational methods to analyze the dynamics of histone PTMs and demonstrate their use in mouse organs during aging. The score that we term "normalized interplay" addresses limitations of the original crosstalk score "interplay" providing a more complete and accurate measure of PTM crosstalk. The second score, ΔI or "directional interplay" is an asymmetric measure quantifying the magnitude and directionality of crosstalk between PTMs. Applying our two-stage scoring approach to data from CrosstalkDB reveals the dynamics of histone H3 modifications during aging.
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Affiliation(s)
- Karl F Poncha
- Verna & Marrs McLean Department of Biochemistry & Molecular Pharmacology, Baylor College of Medicine, Houston, Texas 77030, United States
| | - Alyssa T Paparella
- Verna & Marrs McLean Department of Biochemistry & Molecular Pharmacology, Baylor College of Medicine, Houston, Texas 77030, United States
- Center for Precision Environmental Health, Baylor College of Medicine, Houston, Texas 77030, United States
| | - Nicolas L Young
- Verna & Marrs McLean Department of Biochemistry & Molecular Pharmacology, Baylor College of Medicine, Houston, Texas 77030, United States
- Center for Precision Environmental Health, Baylor College of Medicine, Houston, Texas 77030, United States
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, United States
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3
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Jay A, Pondevida CM, Vahedi G. The epigenetic landscape of fate decisions in T cells. Nat Immunol 2025; 26:544-556. [PMID: 40108419 DOI: 10.1038/s41590-025-02113-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 02/14/2025] [Indexed: 03/22/2025]
Abstract
Specialized T cell subsets mediate adaptive immunity in response to cytokine signaling and specific transcription factor activity. The epigenetic landscape of T cells has an important role in facilitating and establishing T cell fate decisions. Here, we review the interplay between transcription factors, histone modifications, DNA methylation and three-dimensional chromatin organization to define key elements of the epigenetic landscape in T cells. We introduce key technologies in the areas of sequencing, microscopy and proteomics that have enabled the multi-scale profiling of the epigenetic landscape. We highlight the dramatic changes of the epigenetic landscape as multipotent progenitor cells commit to the T cell lineage during development and discuss the epigenetic changes that favor the emergence of CD4+ and CD8+ T cells. Finally, we discuss the inheritance of epigenetic marks and its potential effects on immune responses as well as therapeutic strategies with potential for epigenetic regulation.
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Affiliation(s)
- Atishay Jay
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, USA
| | - Carlos M Pondevida
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, USA
| | - Golnaz Vahedi
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
- Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
- Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
- Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania, Philadelphia, PA, USA.
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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4
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Tang L, Peng S, Zhuang X, He Y, Song Y, Nie H, Zheng C, Pan Z, Lam AK, He M, Shi X, Li B, Xu WW. Tumor Metastasis: Mechanistic Insights and Therapeutic Intervention. MEDCOMM – ONCOLOGY 2025; 4. [DOI: 10.1002/mog2.70012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Accepted: 01/10/2025] [Indexed: 03/04/2025]
Abstract
ABSTRACTMetastasis remains a leading cause of cancer‐related deaths, defined by a complex, multi‐step process in which tumor cells spread and form secondary growths in distant tissues. Despite substantial progress in understanding metastasis, the molecular mechanisms driving this process and the development of effective therapies remain incompletely understood. Elucidating the molecular pathways governing metastasis is essential for the discovery of innovative therapeutic targets. The rapid advancements in sequencing technologies and the expansion of biological databases have significantly deepened our understanding of the molecular drivers of metastasis and associated drug resistance. This review focuses on the molecular drivers of metastasis, particularly the roles of genetic mutations, epigenetic changes, and post‐translational modifications in metastasis progression. We also examine how the tumor microenvironment influences metastatic behavior and explore emerging therapeutic strategies, including targeted therapies and immunotherapies. Finally, we discuss future research directions, stressing the importance of novel treatment approaches and personalized strategies to overcome metastasis and improve patient outcomes. By integrating contemporary insights into the molecular basis of metastasis and therapeutic innovation, this review provides a comprehensive framework to guide future research and clinical advancements in metastatic cancer.
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Affiliation(s)
- Lin Tang
- State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, The Affiliated Traditional Chinese Medicine Hospital Guangzhou Medical University Guangzhou China
| | - Shao‐Cong Peng
- State Key Laboratory of Respiratory Disease, Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes The Fifth Affiliated Hospital of Guangzhou Medical University Guangzhou China
| | - Xiao‐Wan Zhuang
- State Key Laboratory of Respiratory Disease, Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes The Fifth Affiliated Hospital of Guangzhou Medical University Guangzhou China
| | - Yan He
- State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, The Affiliated Traditional Chinese Medicine Hospital Guangzhou Medical University Guangzhou China
| | - Yu‐Xiang Song
- State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, The Affiliated Traditional Chinese Medicine Hospital Guangzhou Medical University Guangzhou China
| | - Hao Nie
- Department of Radiation Oncology, The Fifth Affiliated Hospital Guangzhou Medical University Guangzhou China
| | - Can‐Can Zheng
- State Key Laboratory of Respiratory Disease, Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes The Fifth Affiliated Hospital of Guangzhou Medical University Guangzhou China
| | - Zhen‐Yu Pan
- Department of Radiation Oncology, The Affiliated Huizhou Hospital Guangzhou Medical University Huizhou China
| | - Alfred King‐Yin Lam
- Cancer Molecular Pathology and Griffith Medical School Griffith University Gold Coast Queensland Australia
| | - Ming‐Liang He
- Department of Biomedical Sciences City University of Hong Kong Hong Kong China
| | - Xing‐Yuan Shi
- Department of Radiation Oncology, The Fifth Affiliated Hospital Guangzhou Medical University Guangzhou China
| | - Bin Li
- State Key Laboratory of Respiratory Disease, Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes The Fifth Affiliated Hospital of Guangzhou Medical University Guangzhou China
| | - Wen Wen Xu
- State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, The Affiliated Traditional Chinese Medicine Hospital Guangzhou Medical University Guangzhou China
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5
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Galindo G, Maejima D, DeRoo J, Burlingham SR, Fixen G, Morisaki T, Febvre HP, Hasbrook R, Zhao N, Ghosh S, Mayton EH, Snow CD, Geiss BJ, Ohkawa Y, Sato Y, Kimura H, Stasevich TJ. AI-assisted protein design to rapidly convert antibody sequences to intrabodies targeting diverse peptides and histone modifications. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.06.636921. [PMID: 39975170 PMCID: PMC11839053 DOI: 10.1101/2025.02.06.636921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
Intrabodies are engineered antibodies that function inside living cells, enabling therapeutic, diagnostic, and imaging applications. While powerful, their development has been hindered by challenges associated with their folding, solubility, and stability in the reduced intracellular environment. Here, we present an AI-driven pipeline integrating AlphaFold2, ProteinMPNN, and live-cell screening to optimize antibody framework regions while preserving epitope-binding complementarity-determining regions. Using this approach, we successfully converted 19 out of 26 antibody sequences into functional single-chain variable fragment (scFv) intrabodies, including a panel targeting diverse histone modifications for real-time imaging of chromatin dynamics and gene regulation. Notably, 18 of these 19 sequences had failed to convert using the standard approach, demonstrating the unique effectiveness of our method. As antibody sequence databases expand, our method will accelerate intrabody design, making their development easier, more cost-effective, and broadly accessible for biological research.
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Affiliation(s)
- Gabriel Galindo
- Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO, USA
| | - Daiki Maejima
- School of Life Science and Technology, Institute of Science Tokyo, Yokohama, Japan
| | - Jacob DeRoo
- School of Biomedical Engineering, Colorado State University, Fort Collins, CO, USA
| | - Scott R Burlingham
- Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO, USA
| | - Gretchen Fixen
- Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO, USA
| | - Tatsuya Morisaki
- Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO, USA
| | - Hallie P Febvre
- Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO, USA
| | - Ryan Hasbrook
- Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO, USA
| | - Ning Zhao
- Department of Biochemistry and Molecular Genetics, University of Colorado-Anschutz Medical Campus, Aurora, CO, USA
| | - Soham Ghosh
- School of Biomedical Engineering, Colorado State University, Fort Collins, CO, USA
- Department of Mechanical Engineering, Colorado State University, Fort Collins, CO, USA
| | - E Handly Mayton
- Department of Microbiology, Immunology, & Pathology, Colorado State University, Fort Collins, CO, USA
| | - Christopher D Snow
- Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO, USA
- School of Biomedical Engineering, Colorado State University, Fort Collins, CO, USA
- Department of Chemical & Biological Engineering, Colorado State University, Fort Collins, CO, USA
| | - Brian J Geiss
- School of Biomedical Engineering, Colorado State University, Fort Collins, CO, USA
- Department of Microbiology, Immunology, & Pathology, Colorado State University, Fort Collins, CO, USA
| | - Yasuyuki Ohkawa
- Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - Yuko Sato
- Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
- Cell Biology Center, Institute of Innovative Research, Tokyo Institute of Technology, Yokohama, Japan
| | - Hiroshi Kimura
- School of Life Science and Technology, Institute of Science Tokyo, Yokohama, Japan
- Cell Biology Center, Institute of Innovative Research, Tokyo Institute of Technology, Yokohama, Japan
- Cell Biology Center, Institute of Integrated Research, Institute of Science Tokyo, Yokohama, Japan
| | - Timothy J Stasevich
- Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO, USA
- School of Biomedical Engineering, Colorado State University, Fort Collins, CO, USA
- Department of Chemical & Biological Engineering, Colorado State University, Fort Collins, CO, USA
- Cell Biology Center, Institute of Integrated Research, Institute of Science Tokyo, Yokohama, Japan
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6
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Ali A, Azmat U, Ji Z, Khatoon A, Murtaza B, Akbar K, Irshad U, Raza R, Su Z. Beyond Genes: Epiregulomes as Molecular Commanders in Innate Immunity. Int Immunopharmacol 2024; 142:113149. [PMID: 39278059 DOI: 10.1016/j.intimp.2024.113149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Revised: 08/09/2024] [Accepted: 09/08/2024] [Indexed: 09/17/2024]
Abstract
The natural fastest way to deal with pathogens or danger signals is the innate immune system. This system prevents too much inflammation and tissue damage and efficiently eliminates pathogens. The epiregulome is the chromatin structure influenced by epigenetic factors and linked to cis-regulatory elements (CREs). The epiregulome helps to end the inflammatory response and also assists innate immune cells to show specific action by making cell-specific gene expression patterns. This inspection unfolds two concepts: (1) how epiregulomes are shaped by switching the expression levels of genes, manoeuvre enzyme activity and earmark of chromatin modifiers on specific genes; during and after the infection, and (2) how the expression of specific genes (aids in prompt management of innate cell growth, or the reaction to aggravation and illness) command by epiregulomes that formed during the above process. In this review, the consequences of intrinsic immuno-metabolic remodelling on epiregulomes and potential difficulties in identifying the master epiregulome that regulates innate immunity and inflammation have been discussed.
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Affiliation(s)
- Ashiq Ali
- Department of Histology and Embryology, Shantou University Medical College, China.
| | - Urooj Azmat
- Department of Zoology, Wildlife and Fisheries, University of Agriculture, Faisalabad, Pakistan
| | - Ziyi Ji
- Department of Histology and Embryology, Shantou University Medical College, China
| | - Aisha Khatoon
- Department of Pathology, University of Agriculture Faisalabad, Pakistan
| | - Bilal Murtaza
- School of Bioengineering, Dalian University of Science and Technology, Dalian, China
| | - Kaynaat Akbar
- Department of Zoology, Wildlife and Fisheries, University of Agriculture, Faisalabad, Pakistan
| | - Urooj Irshad
- Department Biological Sciences, Faculty of Sciences, Superior University Lahore, Punjab, Pakistan
| | - Rameen Raza
- Department of Pathology, University of Agriculture Faisalabad, Pakistan
| | - Zhongjing Su
- Department of Histology and Embryology, Shantou University Medical College, China.
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7
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Ueberheide BM, Mollah S, Garcia BA. On the Hunt for the Histone Code. Mol Cell Proteomics 2024; 23:100873. [PMID: 39489218 PMCID: PMC11696663 DOI: 10.1016/j.mcpro.2024.100873] [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: 10/01/2024] [Accepted: 10/24/2024] [Indexed: 11/05/2024] Open
Abstract
Our genome is not made of naked DNA but a fiber (chromatin) composed of DNA and proteins packaged into our chromosomes. The basic building block of chromatin is the nucleosome, which has two copies of each of the proteins called histones (H2A, H2B, H3, and H4) wrapped by 146 base pairs of DNA. Regions of our genetic material are found between the more open (euchromatin) and more compact (heterochromatin) regions of the genome that can be variably accessible to the underlying genes. Furthermore, post-translational modifications (PTMs) on histones, such as on H3, are critical for regulating chromatin accessibility and gene expression. While site-specific antibodies were the tool of choice for histone PTM analysis in the early days (pre-2000s), enter Don Hunt changing the histone PTM field forever. Don's clever thinking brought new innovative mass spectrometry-based approaches to the epigenetics field. His lab's effort led to the discovery of many new histone modifications and methods to facilitate the detection and quantification of histone PTMs, which are still considered state of the art in the proteomics field today. Due to Don's pioneering work in this area, many labs have been able to jump into the epigenetics field and "Hunt" down their own histone targets. A walkthrough of those early histone years in the Hunt Lab is described by three of us who were fortunate enough to be at the right place, at the right time.
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Affiliation(s)
- Beatrix M Ueberheide
- Proteomics Laboratory, Division of Advanced Research Technologies, Department of Biochemistry and Molecular Pharmacology, New York University Langone Health Center, New York, New York, USA; Department of Neurology, New York University Langone Health Center, New York, New York, USA.
| | | | - Benjamin A Garcia
- Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St Louis, Missouri, USA.
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8
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Korolenko A, Skinner MK. Generational stability of epigenetic transgenerational inheritance facilitates adaptation and evolution. Epigenetics 2024; 19:2380929. [PMID: 39104183 PMCID: PMC11305060 DOI: 10.1080/15592294.2024.2380929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 06/29/2024] [Accepted: 07/11/2024] [Indexed: 08/07/2024] Open
Abstract
The epigenome and epigenetic inheritance were not included in the original modern synthesis theory or more recent extended evolutionary synthesis of evolution. In a broad range of species, the environment has been shown to play a significant role in natural selection, which more recently has been shown to occur through epigenetic alterations and epigenetic inheritance. However, even with this evidence, the field of epigenetics and epigenetic inheritance has been left out of modern evolutionary synthesis, as well as other current evolutionary models. Epigenetic mechanisms can direct the regulation of genetic processes (e.g. gene expression) and also can be directly changed by the environment. In contrast, DNA sequence cannot be directly altered by the environment. The goal of this review is to present the evidence of how epigenetics and epigenetic inheritance can alter phenotypic variation in numerous species. This can occur at a significantly higher frequency than genetic change, so correlates with the frequency of evolutionary change. In addition, the concept and importance of generational stability of transgenerational inheritance is incorporated into evolutionary theory. For there to be a better understanding of evolutionary biology, we must incorporate all aspects of molecular (e.g. genetics and epigenetics) and biological sciences (e.g. environment and adaptation).
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Affiliation(s)
- Alexandra Korolenko
- Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, WA, USA
| | - Michael K. Skinner
- Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, WA, USA
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9
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Poncha KF, Paparella AT, Young NL. Normalized and Directional Interplay Scoring for the Interrogation of Proteoform Data. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.18.624157. [PMID: 39605462 PMCID: PMC11601473 DOI: 10.1101/2024.11.18.624157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/29/2024]
Abstract
Histone proteoforms, often presenting multiple co-occurring post-translational modifications (PTMs), are central to chromatin regulation and gene expression. A proteoform is a specific form of a protein that includes variations arising from genetic changes, alternative RNA splicing, proteolytic processing, and PTMs. Genomic context-dependent histone proteoforms define the histone code, influencing cellular phenotype by dictating interactions with DNA and chromatin-associated proteins. Understanding the dynamics of histone proteoforms is essential for elucidating chromatin-based regulatory mechanisms. Advances in middle-down and top-down proteomics methods enable accurate identification and quantitation of hundreds to thousands of proteoforms in a single run. However, the resulting data complexity presents significant challenges for analysis and visualization. Here, we introduce new computational methods to analyze the dynamics of histone PTMs and demonstrate their use in mouse organs during aging. We have developed and benchmarked two novel PTM crosstalk scores. The score that we term 'Normalized Interplay' addresses limitations of the original crosstalk score 'Interplay' providing a more complete and accurate measure of PTM crosstalk. The second score, 'delta I' or Directional Interplay is an asymmetric measure quantifying the magnitude and directionality of crosstalk between PTMs. Applying our two-stage scoring approach to data from CrosstalkDB, a community resource that curates proteoform-level data, reveals the dynamics of histone H3 modifications during aging. The source code is available under an Apache license at https://github.com/k-p4/ptm_interplay_scoring.
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Affiliation(s)
- Karl F Poncha
- Verna & Marrs McLean Department of Biochemistry & Molecular Pharmacology, Baylor College of Medicine, Houston Texas
| | - Alyssa T. Paparella
- Verna & Marrs McLean Department of Biochemistry & Molecular Pharmacology, Baylor College of Medicine, Houston Texas
| | - Nicolas L. Young
- Verna & Marrs McLean Department of Biochemistry & Molecular Pharmacology, Baylor College of Medicine, Houston Texas
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
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10
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Mészár Z, Erdei V, Szücs P, Varga A. Epigenetic Regulation and Molecular Mechanisms of Burn Injury-Induced Nociception in the Spinal Cord of Mice. Int J Mol Sci 2024; 25:8510. [PMID: 39126078 PMCID: PMC11313498 DOI: 10.3390/ijms25158510] [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: 07/21/2024] [Revised: 08/02/2024] [Accepted: 08/02/2024] [Indexed: 08/12/2024] Open
Abstract
Epigenetic mechanisms, including histone post-translational modifications (PTMs), play a critical role in regulating pain perception and the pathophysiology of burn injury. However, the epigenetic regulation and molecular mechanisms underlying burn injury-induced pain remain insufficiently explored. Spinal dynorphinergic (Pdyn) neurons contribute to heat hyperalgesia induced by severe scalding-type burn injury through p-S10H3-dependent signaling. Beyond p-S10H3, burn injury may impact various other histone H3 PTMs. Double immunofluorescent staining and histone H3 protein analyses demonstrated significant hypermethylation at H3K4me1 and H3K4me3 sites and hyperphosphorylation at S10H3 within the spinal cord. By analyzing Pdyn neurons in the spinal dorsal horn, we found evidence of chromatin activation with a significant elevation in p-S10H3 immunoreactivity. We used RNA-seq analysis to compare the effects of burn injury and formalin-induced inflammatory pain on spinal cord transcriptomic profiles. We identified 98 DEGs for burn injury and 86 DEGs for formalin-induced inflammatory pain. A limited number of shared differentially expressed genes (DEGs) suggest distinct central pain processing mechanisms between burn injury and formalin models. KEGG pathway analysis supported this divergence, with burn injury activating Wnt signaling. This study enhances our understanding of burn injury mechanisms and uncovers converging and diverging pathways in pain models with different origins.
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Affiliation(s)
- Zoltán Mészár
- Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary; (Z.M.); (P.S.)
| | - Virág Erdei
- Department of Radiology, Central Hospital of Northern Pest—Military Hospital, H-1134 Budapest, Hungary;
| | - Péter Szücs
- Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary; (Z.M.); (P.S.)
- HUN-REN-DE Neuroscience Research Group, H-4032 Debrecen, Hungary
| | - Angelika Varga
- Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary; (Z.M.); (P.S.)
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11
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Phillips M, Malone KL, Boyle BW, Montgomery C, Kressy IA, Joseph FM, Bright KM, Boyson SP, Chang S, Nix JC, Young NL, Jeffers V, Frietze S, Glass KC. Impact of Combinatorial Histone Modifications on Acetyllysine Recognition by the ATAD2 and ATAD2B Bromodomains. J Med Chem 2024; 67:8186-8200. [PMID: 38733345 PMCID: PMC11149620 DOI: 10.1021/acs.jmedchem.4c00210] [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] [Indexed: 05/13/2024]
Abstract
The ATPase family AAA+ domain containing 2 (ATAD2) protein and its paralog ATAD2B have a C-terminal bromodomain (BRD) that functions as a reader of acetylated lysine residues on histone proteins. Using a structure-function approach, we investigated the ability of the ATAD2/B BRDs to select acetylated lysine among multiple histone post-translational modifications. The ATAD2B BRD can bind acetylated histone ligands that also contain adjacent methylation or phosphorylation marks, while the presence of these modifications significantly weakened the acetyllysine binding activity of the ATAD2 BRD. Our structural studies provide mechanistic insights into how ATAD2/B BRD-binding pocket residues coordinate the acetyllysine group in the context of adjacent post-translational modifications. Furthermore, we investigated how sequence changes in amino acids of the histone ligands impact the recognition of an adjacent acetyllysine residue. Our study highlights how the interplay between multiple combinations of histone modifications influences the reader activity of the ATAD2/B BRDs, resulting in distinct binding modes.
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Affiliation(s)
- Margaret Phillips
- Department of Pharmacology, Larner College of Medicine, University of Vermont, Burlington, Vermont 05405, United States
- Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Colchester, Vermont 05446, United States
| | - Kiera L Malone
- Department of Pharmacology, Larner College of Medicine, University of Vermont, Burlington, Vermont 05405, United States
| | - Brian W Boyle
- Department of Pharmacology, Larner College of Medicine, University of Vermont, Burlington, Vermont 05405, United States
| | - Cameron Montgomery
- Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Colchester, Vermont 05446, United States
| | - Isabelle A Kressy
- Department of Pharmacology, Larner College of Medicine, University of Vermont, Burlington, Vermont 05405, United States
| | - Faith M Joseph
- Verna & Marrs McLean Department of Biochemistry & Molecular Pharmacology, Baylor College of Medicine, Houston, Texas 77030, United States
- Translational Biology and Molecular Medicine Graduate Program, Baylor College of Medicine, Houston, Texas 77030, United States
| | - Kathleen M Bright
- Department of Biomedical and Health Sciences, University of Vermont, Burlington, Vermont 05405, United States
| | - Samuel P Boyson
- Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Colchester, Vermont 05446, United States
| | - Sunsik Chang
- Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Colchester, Vermont 05446, United States
| | - Jay C Nix
- Molecular Biology Consortium, Advanced Light Source, Berkeley, California 94720, United States
| | - Nicolas L Young
- Verna & Marrs McLean Department of Biochemistry & Molecular Pharmacology, Baylor College of Medicine, Houston, Texas 77030, United States
- Translational Biology and Molecular Medicine Graduate Program, Baylor College of Medicine, Houston, Texas 77030, United States
| | - Victoria Jeffers
- Department of Molecular, Cellular and Biomedical Sciences, University of New Hampshire, Durham, New Hampshire 03824, United States
| | - Seth Frietze
- Department of Biomedical and Health Sciences, University of Vermont, Burlington, Vermont 05405, United States
| | - Karen C Glass
- Department of Pharmacology, Larner College of Medicine, University of Vermont, Burlington, Vermont 05405, United States
- Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Colchester, Vermont 05446, United States
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12
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Taylor BC, Steinthal LH, Dias M, Yalamanchili HK, Ochsner SA, Zapata GE, Mehta NR, McKenna NJ, Young NL, Nuotio-Antar AM. Histone proteoform analysis reveals epigenetic changes in adult mouse brown adipose tissue in response to cold stress. Epigenetics Chromatin 2024; 17:12. [PMID: 38678237 PMCID: PMC11055387 DOI: 10.1186/s13072-024-00536-8] [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: 02/09/2024] [Accepted: 04/09/2024] [Indexed: 04/29/2024] Open
Abstract
BACKGROUND Regulation of the thermogenic response by brown adipose tissue (BAT) is an important component of energy homeostasis with implications for the treatment of obesity and diabetes. Our preliminary analyses of RNA-Seq data uncovered many nodes representing epigenetic modifiers that are altered in BAT in response to chronic thermogenic activation. Thus, we hypothesized that chronic thermogenic activation broadly alters epigenetic modifications of DNA and histones in BAT. RESULTS Motivated to understand how BAT function is regulated epigenetically, we developed a novel method for the first-ever unbiased top-down proteomic quantitation of histone modifications in BAT and validated our results with a multi-omic approach. To test our hypothesis, wildtype male C57BL/6J mice were housed under chronic conditions of thermoneutral temperature (TN, 28°C), mild cold/room temperature (RT, 22°C), or severe cold (SC, 8°C) and BAT was analyzed for DNA methylation and histone modifications. Methylation of promoters and intragenic regions in genomic DNA decrease in response to chronic cold exposure. Integration of DNA methylation and RNA expression datasets suggest a role for epigenetic modification of DNA in regulation of gene expression in response to cold. In response to cold housing, we observe increased bulk acetylation of histones H3.2 and H4, increased histone H3.2 proteoforms with di- and trimethylation of lysine 9 (K9me2 and K9me3), and increased histone H4 proteoforms with acetylation of lysine 16 (K16ac) in BAT. CONCLUSIONS Our results reveal global epigenetically-regulated transcriptional "on" and "off" signals in murine BAT in response to varying degrees of chronic cold stimuli and establish a novel methodology to quantitatively study histones in BAT, allowing for direct comparisons to decipher mechanistic changes during the thermogenic response. Additionally, we make histone PTM and proteoform quantitation, RNA splicing, RRBS, and transcriptional footprint datasets available as a resource for future research.
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Affiliation(s)
- Bethany C Taylor
- Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, TX, USA
| | - Loic H Steinthal
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Division of Nutrition, Baylor College of Medicine, Houston, TX, USA
| | - Michelle Dias
- Department of Pediatrics, Division of Neurology, Baylor College of Medicine, Houston, TX, USA
| | - Hari Krishna Yalamanchili
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Division of Nutrition, Baylor College of Medicine, Houston, TX, USA
- Department of Pediatrics, Division of Neurology, Baylor College of Medicine, Houston, TX, USA
- Jan and Dan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA
| | - Scott A Ochsner
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
| | - Gladys E Zapata
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Division of Nutrition, Baylor College of Medicine, Houston, TX, USA
| | - Nitesh R Mehta
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Division of Nutrition, Baylor College of Medicine, Houston, TX, USA
| | - Neil J McKenna
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
| | - Nicolas L Young
- Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, TX, USA.
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
- Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX, USA.
| | - Alli M Nuotio-Antar
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Division of Nutrition, Baylor College of Medicine, Houston, TX, USA.
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13
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Taylor BC, Steinthal LH, Dias M, Yalamanchili HK, Ochsner SA, Zapata GE, Mehta NR, McKenna NJ, Young NL, Nuotio-Antar AM. Histone proteoform analysis reveals epigenetic changes in adult mouse brown adipose tissue in response to cold stress. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.07.30.551059. [PMID: 38328142 PMCID: PMC10849524 DOI: 10.1101/2023.07.30.551059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2024]
Abstract
Regulation of the thermogenic response by brown adipose tissue (BAT) is an important component of energy homeostasis with implications for the treatment of obesity and diabetes. Our preliminary analyses uncovered many nodes representing epigenetic modifiers that are altered in BAT in response to chronic thermogenic activation. Thus, we hypothesized that chronic thermogenic activation broadly alters epigenetic modifications of DNA and histones in BAT. Motivated to understand how BAT function is regulated epigenetically, we developed a novel method for the first-ever unbiased top-down proteomic quantitation of histone modifications in BAT and validated our results with a multi-omic approach. To test our hypothesis, wildtype male C57BL/6J mice were housed under chronic conditions of thermoneutral temperature (TN, 28.8°C), mild cold/room temperature (RT, 22°C), or severe cold (SC, 8°C) and BAT was analyzed for DNA methylation and histone modifications. Methylation of promoters and intragenic regions in genomic DNA decrease in response to chronic cold exposure. Integration of DNA methylation and RNA expression data suggest a role for epigenetic modification of DNA in gene regulation in response to cold. In response to cold housing, we observe increased bulk acetylation of histones H3.2 and H4, increased histone H3.2 proteoforms with di- and trimethylation of lysine 9 (K9me2 and K9me3), and increased histone H4 proteoforms with acetylation of lysine 16 (K16ac) in BAT. Taken together, our results reveal global epigenetically-regulated transcriptional "on" and "off" signals in murine BAT in response to varying degrees of chronic cold stimuli and establish a novel methodology to quantitatively study histones in BAT, allowing for direct comparisons to decipher mechanistic changes during the thermogenic response. Additionally, we make histone PTM and proteoform quantitation, RNA splicing, RRBS, and transcriptional footprint datasets available as a resource for future research.
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Affiliation(s)
- Bethany C. Taylor
- Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, TX
| | - Loic H. Steinthal
- Children’s Nutrition Research Center, Baylor College of Medicine, Houston, TX
| | - Michelle Dias
- Jan and Dan Duncan Neurological Research Institute, Baylor College of Medicine, Houston, TX
| | - Hari K. Yalamanchili
- Children’s Nutrition Research Center, Baylor College of Medicine, Houston, TX
- Jan and Dan Duncan Neurological Research Institute, Baylor College of Medicine, Houston, TX
| | - Scott A. Ochsner
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
| | - Gladys E. Zapata
- Children’s Nutrition Research Center, Baylor College of Medicine, Houston, TX
| | - Nitesh R. Mehta
- Children’s Nutrition Research Center, Baylor College of Medicine, Houston, TX
| | - Neil J. McKenna
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
| | - Nicolas L. Young
- Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, TX
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
- Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX
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14
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Zhang R, Xie X, Ni D, Wang H, Li J, Xiao W. MT-EpiPred: Multitask Learning for Prediction of Small-Molecule Epigenetic Modulators. J Chem Inf Model 2024; 64:110-118. [PMID: 38109786 DOI: 10.1021/acs.jcim.3c01368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2023]
Abstract
Epigenetic modulators play an increasingly crucial role in the treatment of various diseases. In this case, it is imperative to systematically investigate the activity of these agents and understand their influence on the entire epigenetic regulatory network rather than solely concentrate on individual targets. This work introduces MT-EpiPred, a multitask learning method capable of predicting the activity of compounds against 78 epigenetic targets. MT-EpiPred demonstrated outstanding performance, boasting an average auROC of 0.915 and the ability to handle few-shot targets. In comparison to the existing method, MT-EpiPred not only expands the target pool but also achieves superior predictive performance with the same data set. MT-EpiPred was then applied to predict the epigenetic target of a newly synthesized compound (1), where the molecular target was unknown. The method identified KDM4D as a potential target, which was subsequently validated through an in vitro enzyme inhibition assay, revealing an IC50 of 4.8 μM. The MT-EpiPred method has been implemented in the web server MT-EpiPred (http://epipred.com), providing free accessibility. In summary, this work presents a convenient and accurate tool for discovering novel small-molecule epigenetic modulators, particularly in the development of selective inhibitors and evaluating the impact of these inhibitors over a broad epigenetic network.
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Affiliation(s)
- Ruihan Zhang
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Key Laboratory of Research and Development for Natural Products; The Cloud Computing Engineering Research Center of Yunnan Province; Key Laboratory of Software Engineering of Yunnan Province; School of Software; School of Pharmacy, Yunnan University, Kunming 650500, P. R. China
| | - Xingran Xie
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Key Laboratory of Research and Development for Natural Products; The Cloud Computing Engineering Research Center of Yunnan Province; Key Laboratory of Software Engineering of Yunnan Province; School of Software; School of Pharmacy, Yunnan University, Kunming 650500, P. R. China
| | - Dongxuan Ni
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Key Laboratory of Research and Development for Natural Products; The Cloud Computing Engineering Research Center of Yunnan Province; Key Laboratory of Software Engineering of Yunnan Province; School of Software; School of Pharmacy, Yunnan University, Kunming 650500, P. R. China
| | - Hairong Wang
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Key Laboratory of Research and Development for Natural Products; The Cloud Computing Engineering Research Center of Yunnan Province; Key Laboratory of Software Engineering of Yunnan Province; School of Software; School of Pharmacy, Yunnan University, Kunming 650500, P. R. China
| | - Jin Li
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Key Laboratory of Research and Development for Natural Products; The Cloud Computing Engineering Research Center of Yunnan Province; Key Laboratory of Software Engineering of Yunnan Province; School of Software; School of Pharmacy, Yunnan University, Kunming 650500, P. R. China
| | - Weilie Xiao
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Key Laboratory of Research and Development for Natural Products; The Cloud Computing Engineering Research Center of Yunnan Province; Key Laboratory of Software Engineering of Yunnan Province; School of Software; School of Pharmacy, Yunnan University, Kunming 650500, P. R. China
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15
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Colón-Caraballo M, Flores-Caldera I. Translational aspects of the endometriosis epigenome. EPIGENETICS IN HUMAN DISEASE 2024:883-929. [DOI: 10.1016/b978-0-443-21863-7.00008-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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16
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Kumari S, Gupta R, Ambasta RK, Kumar P. Emerging trends in post-translational modification: Shedding light on Glioblastoma multiforme. Biochim Biophys Acta Rev Cancer 2023; 1878:188999. [PMID: 37858622 DOI: 10.1016/j.bbcan.2023.188999] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 10/06/2023] [Accepted: 10/06/2023] [Indexed: 10/21/2023]
Abstract
Recent multi-omics studies, including proteomics, transcriptomics, genomics, and metabolomics have revealed the critical role of post-translational modifications (PTMs) in the progression and pathogenesis of Glioblastoma multiforme (GBM). Further, PTMs alter the oncogenic signaling events and offer a novel avenue in GBM therapeutics research through PTM enzymes as potential biomarkers for drug targeting. In addition, PTMs are critical regulators of chromatin architecture, gene expression, and tumor microenvironment (TME), that play a crucial function in tumorigenesis. Moreover, the implementation of artificial intelligence and machine learning algorithms enhances GBM therapeutics research through the identification of novel PTM enzymes and residues. Herein, we briefly explain the mechanism of protein modifications in GBM etiology, and in altering the biologics of GBM cells through chromatin remodeling, modulation of the TME, and signaling pathways. In addition, we highlighted the importance of PTM enzymes as therapeutic biomarkers and the role of artificial intelligence and machine learning in protein PTM prediction.
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Affiliation(s)
- Smita Kumari
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological, University, India
| | - Rohan Gupta
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological, University, India; School of Medicine, University of South Carolina, Columbia, SC, United States of America
| | - Rashmi K Ambasta
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological, University, India; Department of Biotechnology and Microbiology, SRM University, Sonepat, Haryana, India.
| | - Pravir Kumar
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological, University, India.
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17
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Pienkowski T, Kowalczyk T, Cysewski D, Kretowski A, Ciborowski M. Glioma and post-translational modifications: A complex relationship. Biochim Biophys Acta Rev Cancer 2023; 1878:189009. [PMID: 37913943 DOI: 10.1016/j.bbcan.2023.189009] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 10/17/2023] [Accepted: 10/17/2023] [Indexed: 11/03/2023]
Abstract
Post-translational modifications (PTMs) are common covalent processes in biochemical pathways that alter protein function and activity. These modifications occur through proteolytic cleavage or attachment of modifying groups, such as phosphoryl, methyl, glycosyl, or acetyl groups, with one or more amino acid residues of a single protein. Some PTMs also present crosstalk abilities that affect both protein functionality and structure, creating new proteoforms. Any alteration in organism homeostasis may be a cancer hallmark. Cataloging PTMs and consequently, emerging proteoforms, present new therapeutic targets, approaches, and opportunities to discover additional discriminatory biomarkers in disease diagnostics. In this review, we focus on experimentally confirmed PTMs and their potential crosstalk in glioma research to introduce new opportunities for this tumor type, which emerge within the PTMomics area.
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Affiliation(s)
- Tomasz Pienkowski
- Clinical Research Centre, Medical University of Bialystok, M. Sklodowskiej-Curie 24a, 15-276 Bialystok, Poland
| | - Tomasz Kowalczyk
- Clinical Research Centre, Medical University of Bialystok, M. Sklodowskiej-Curie 24a, 15-276 Bialystok, Poland; Department of Medical Microbiology and Nanobiomedical Engineering, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland
| | - Dominik Cysewski
- Clinical Research Centre, Medical University of Bialystok, M. Sklodowskiej-Curie 24a, 15-276 Bialystok, Poland
| | - Adam Kretowski
- Clinical Research Centre, Medical University of Bialystok, M. Sklodowskiej-Curie 24a, 15-276 Bialystok, Poland; Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, M. Sklodowskiej-Curie 24a, 15-276 Bialystok, Poland
| | - Michal Ciborowski
- Clinical Research Centre, Medical University of Bialystok, M. Sklodowskiej-Curie 24a, 15-276 Bialystok, Poland.
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18
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de Almeida RF, Lucena ACR, Batista M, Marchini FK, de Godoy LMF. Non-histone protein methylation in Trypanosoma cruzi epimastigotes. Proteomics 2023; 23:e2200230. [PMID: 37183273 DOI: 10.1002/pmic.202200230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 04/27/2023] [Accepted: 04/28/2023] [Indexed: 05/16/2023]
Abstract
Post-translational methylation of proteins, which occurs in arginines and lysines, modulates several biological processes at different levels of cell signaling. Recently, methylation has been demonstrated in the regulation beyond histones, for example, in the dynamics of protein-protein and protein-nucleic acid interactions. However, the presence and role of non-histone methylation in Trypanosoma cruzi, the etiologic agent of Chagas disease, has not yet been elucidated. Here, we applied mass spectrometry-based-proteomics (LC-MS/MS) to profile the methylproteome of T. cruzi epimastigotes, describing a total of 1252 methyl sites in 824 proteins. Functional enrichment and protein-protein interaction analysis show that protein methylation impacts important biological processes of the parasite, such as translation, RNA and DNA binding, amino acid, and carbohydrate metabolism. In addition, 171 of the methylated proteins were previously reported to bear phosphorylation sites in T. cruzi, including flagellar proteins and RNA binding proteins, indicating that there may be an interplay between these different modifications in non-histone proteins. Our results show that a broad spectrum of functions is affected by methylation in T. cruzi, indicating its potential to impact important processes in the biology of the parasite and other trypanosomes.
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Affiliation(s)
- Rafael Fogaça de Almeida
- Laboratório de Biologia Molecular e Sistêmica de Tripanossomatídeos, Instituto Carlos Chagas, Fundação Oswaldo Cruz, Curitiba, Parana, Brazil
| | - Aline Castro Rodrigues Lucena
- Laboratório de Ciências e Tecnologias Aplicadas em Saúde, Instituto Carlos Chagas, Fundação Oswaldo Cruz, Curitiba, Parana, Brazil
| | - Michel Batista
- Laboratório de Ciências e Tecnologias Aplicadas em Saúde, Instituto Carlos Chagas, Fundação Oswaldo Cruz, Curitiba, Parana, Brazil
- Plataforma de Espectrometria de Massas, Instituto Carlos Chagas, Fundação Oswaldo Cruz, Curitiba, Parana, Brazil
| | - Fabricio Klerynton Marchini
- Laboratório de Ciências e Tecnologias Aplicadas em Saúde, Instituto Carlos Chagas, Fundação Oswaldo Cruz, Curitiba, Parana, Brazil
- Plataforma de Espectrometria de Massas, Instituto Carlos Chagas, Fundação Oswaldo Cruz, Curitiba, Parana, Brazil
| | - Lyris Martins Franco de Godoy
- Laboratório de Biologia Molecular e Sistêmica de Tripanossomatídeos, Instituto Carlos Chagas, Fundação Oswaldo Cruz, Curitiba, Parana, Brazil
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19
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Chaddad A, Tan G, Liang X, Hassan L, Rathore S, Desrosiers C, Katib Y, Niazi T. Advancements in MRI-Based Radiomics and Artificial Intelligence for Prostate Cancer: A Comprehensive Review and Future Prospects. Cancers (Basel) 2023; 15:3839. [PMID: 37568655 PMCID: PMC10416937 DOI: 10.3390/cancers15153839] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 07/25/2023] [Accepted: 07/26/2023] [Indexed: 08/13/2023] Open
Abstract
The use of multiparametric magnetic resonance imaging (mpMRI) has become a common technique used in guiding biopsy and developing treatment plans for prostate lesions. While this technique is effective, non-invasive methods such as radiomics have gained popularity for extracting imaging features to develop predictive models for clinical tasks. The aim is to minimize invasive processes for improved management of prostate cancer (PCa). This study reviews recent research progress in MRI-based radiomics for PCa, including the radiomics pipeline and potential factors affecting personalized diagnosis. The integration of artificial intelligence (AI) with medical imaging is also discussed, in line with the development trend of radiogenomics and multi-omics. The survey highlights the need for more data from multiple institutions to avoid bias and generalize the predictive model. The AI-based radiomics model is considered a promising clinical tool with good prospects for application.
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Affiliation(s)
- Ahmad Chaddad
- School of Artificial Intelligence, Guilin Universiy of Electronic Technology, Guilin 541004, China
- The Laboratory for Imagery, Vision and Artificial Intelligence, École de Technologie Supérieure (ETS), Montreal, QC H3C 1K3, Canada
| | - Guina Tan
- School of Artificial Intelligence, Guilin Universiy of Electronic Technology, Guilin 541004, China
| | - Xiaojuan Liang
- School of Artificial Intelligence, Guilin Universiy of Electronic Technology, Guilin 541004, China
| | - Lama Hassan
- School of Artificial Intelligence, Guilin Universiy of Electronic Technology, Guilin 541004, China
| | | | - Christian Desrosiers
- The Laboratory for Imagery, Vision and Artificial Intelligence, École de Technologie Supérieure (ETS), Montreal, QC H3C 1K3, Canada
| | - Yousef Katib
- Department of Radiology, Taibah University, Al Madinah 42361, Saudi Arabia
| | - Tamim Niazi
- Lady Davis Institute for Medical Research, McGill University, Montreal, QC H3T 1E2, Canada
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20
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Jain K, Marunde MR, Burg JM, Gloor SL, Joseph FM, Poncha KF, Gillespie ZB, Rodriguez KL, Popova IK, Hall NW, Vaidya A, Howard SA, Taylor HF, Mukhsinova L, Onuoha UC, Patteson EF, Cooke SW, Taylor BC, Weinzapfel EN, Cheek MA, Meiners MJ, Fox GC, Namitz KEW, Cowles MW, Krajewski K, Sun ZW, Cosgrove MS, Young NL, Keogh MC, Strahl BD. An acetylation-mediated chromatin switch governs H3K4 methylation read-write capability. eLife 2023; 12:e82596. [PMID: 37204295 PMCID: PMC10229121 DOI: 10.7554/elife.82596] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 05/18/2023] [Indexed: 05/20/2023] Open
Abstract
In nucleosomes, histone N-terminal tails exist in dynamic equilibrium between free/accessible and collapsed/DNA-bound states. The latter state is expected to impact histone N-termini availability to the epigenetic machinery. Notably, H3 tail acetylation (e.g. K9ac, K14ac, K18ac) is linked to increased H3K4me3 engagement by the BPTF PHD finger, but it is unknown if this mechanism has a broader extension. Here, we show that H3 tail acetylation promotes nucleosomal accessibility to other H3K4 methyl readers, and importantly, extends to H3K4 writers, notably methyltransferase MLL1. This regulation is not observed on peptide substrates yet occurs on the cis H3 tail, as determined with fully-defined heterotypic nucleosomes. In vivo, H3 tail acetylation is directly and dynamically coupled with cis H3K4 methylation levels. Together, these observations reveal an acetylation 'chromatin switch' on the H3 tail that modulates read-write accessibility in nucleosomes and resolves the long-standing question of why H3K4me3 levels are coupled with H3 acetylation.
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Affiliation(s)
- Kanishk Jain
- Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill of MedicineChapel HillUnited States
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, School of MedicineChapel HillUnited States
| | | | | | | | - Faith M Joseph
- Verna & Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of MedicineHoustonUnited States
| | - Karl F Poncha
- Verna & Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of MedicineHoustonUnited States
| | | | | | | | | | | | | | | | | | | | | | - Spencer W Cooke
- Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill of MedicineChapel HillUnited States
| | - Bethany C Taylor
- Verna & Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of MedicineHoustonUnited States
| | | | | | | | - Geoffrey C Fox
- Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, School of MedicineChapel HillUnited States
| | | | | | - Krzysztof Krajewski
- Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill of MedicineChapel HillUnited States
| | | | - Michael S Cosgrove
- Department of Biochemistry and Molecular Biology, Upstate Medical UniversitySyracuseUnited States
| | - Nicolas L Young
- Verna & Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of MedicineHoustonUnited States
| | | | - Brian D Strahl
- Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill of MedicineChapel HillUnited States
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, School of MedicineChapel HillUnited States
- Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, School of MedicineChapel HillUnited States
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21
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Kachhawaha AS, Mishra S, Tiwari AK. Epigenetic control of heredity. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2023; 198:25-60. [PMID: 37225323 DOI: 10.1016/bs.pmbts.2023.03.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/26/2023]
Abstract
Epigenetics is the field of science that deals with the study of changes in gene function that do not involve changes in DNA sequence and are heritable while epigenetics inheritance is the process of transmission of epigenetic modifications to the next generation. It can be transient, intergenerational, or transgenerational. There are various epigenetic modifications involving mechanisms such as DNA methylation, histone modification, and noncoding RNA expression, all of which are inheritable. In this chapter, we summarize the information on epigenetic inheritance, its mechanism, inheritance studies on various organisms, factors affecting epigenetic modifications and their inheritance, and the role of epigenetic inheritance in the heritability of diseases.
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Affiliation(s)
- Akanksha Singh Kachhawaha
- Laboratory of Forensic Chemistry & Toxicology, School of Forensic Sciences, National Forensic Sciences University (NFSU), Gandhinagar, Gujarat, India
| | - Sarita Mishra
- Laboratory of Forensic Chemistry & Toxicology, School of Forensic Sciences, National Forensic Sciences University (NFSU), Gandhinagar, Gujarat, India
| | - Anand Krishna Tiwari
- Genetics & Developmental Biology Laboratory, Department of Biotechnology & Bioengineering, Institute of Advanced Research, Gandhinagar, Gujarat, India.
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Taylor BC, Young NL. Histone H4 proteoforms and post-translational modifications in the Mus musculus brain with quantitative comparison of ages and brain regions. Anal Bioanal Chem 2023; 415:1627-1639. [PMID: 36754872 PMCID: PMC10165947 DOI: 10.1007/s00216-023-04555-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 12/08/2022] [Accepted: 01/18/2023] [Indexed: 02/10/2023]
Abstract
Histone proteins are essential to the regulation of the eukaryotic genome. Histone post-translational modifications (PTMs) and single-molecule combinations of these modifications (proteoforms) allow for the regulation of many DNA-templated processes, most notably transcription. Histone H4 is a part of the core histone octamer, which packages DNA into nucleosomes. Top-down proteomics allows for the inquiry of the epigenetic landscape with proteoform-level specificity. Although these approaches are well-demonstrated ex vivo, our knowledge of in vivo histone proteoform biology remains sparse. Here, we demonstrate the first in vivo quantitative top-down analysis of histone H4 and analyze the forebrains and hindbrains of differently aged mice. This reveals novel differences between the mouse forebrain and hindbrain and region-specific changes during adolescence in histone H4 PTMs and proteoforms. At 25 days of age (P25), histone H4 of the hindbrain is more acetylated than the forebrain. At 47 days of age (P47), there are fewer significant differences in histone H4 PTMs and their combinations between regions. Histone H4 of the forebrain is more acetylated in P47 than in P25 forebrains. Hindbrains exhibit the opposite difference with histone H4 of the P25 hindbrain being more acetylated than that of P47 hindbrains. These differences are mainly driven by less abundant hyperacetylated proteoforms. Transcription of histone acetyltransferases such as p300, CBP, and HAT1 is known to be higher in cortical neurons, consistent with the observed acetylation levels. Lysine 20 methylation (K20me1, K20me2, and K20me3) is notably invariant with brain region and age difference.
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Affiliation(s)
- Bethany C Taylor
- Verna & Marrs McLean Department of Biochemistry & Molecular Biology, Baylor College of Medicine, One Baylor Plaza, MS-125, Houston, TX, 77030-3411, USA
| | - Nicolas L Young
- Verna & Marrs McLean Department of Biochemistry & Molecular Biology, Baylor College of Medicine, One Baylor Plaza, MS-125, Houston, TX, 77030-3411, USA.
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
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Abstract
BACKGROUND Autoimmune hepatitis has an unknown cause and genetic associations that are not disease-specific or always present. Clarification of its missing causality and heritability could improve prevention and management strategies. AIMS Describe the key epigenetic and genetic mechanisms that could account for missing causality and heritability in autoimmune hepatitis; indicate the prospects of these mechanisms as pivotal factors; and encourage investigations of their pathogenic role and therapeutic potential. METHODS English abstracts were identified in PubMed using multiple key search phases. Several hundred abstracts and 210 full-length articles were reviewed. RESULTS Environmental induction of epigenetic changes is the prime candidate for explaining the missing causality of autoimmune hepatitis. Environmental factors (diet, toxic exposures) can alter chromatin structure and the production of micro-ribonucleic acids that affect gene expression. Epistatic interaction between unsuspected genes is the prime candidate for explaining the missing heritability. The non-additive, interactive effects of multiple genes could enhance their impact on the propensity and phenotype of autoimmune hepatitis. Transgenerational inheritance of acquired epigenetic marks constitutes another mechanism of transmitting parental adaptations that could affect susceptibility. Management strategies could range from lifestyle adjustments and nutritional supplements to precision editing of the epigenetic landscape. CONCLUSIONS Autoimmune hepatitis has a missing causality that might be explained by epigenetic changes induced by environmental factors and a missing heritability that might reflect epistatic gene interactions or transgenerational transmission of acquired epigenetic marks. These unassessed or under-evaluated areas warrant investigation.
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Affiliation(s)
- Albert J Czaja
- Mayo Clinic College of Medicine and Science, Rochester, MN, USA.
- Professor Emeritus of Medicine, Mayo Clinic College of Medicine and Science, 200 First Street SW, Rochester, MN, 55905, USA.
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24
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Li ASM, Homsi C, Bonneil E, Thibault P, Verreault A, Vedadi M. Histone H4K20 monomethylation enables recombinant nucleosome methylation by PRMT1 in vitro. BIOCHIMICA ET BIOPHYSICA ACTA. GENE REGULATORY MECHANISMS 2023; 1866:194922. [PMID: 36822575 DOI: 10.1016/j.bbagrm.2023.194922] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 02/10/2023] [Accepted: 02/13/2023] [Indexed: 02/23/2023]
Abstract
Protein arginine methyltransferases (PRMTs) catalyze the transfer of methyl groups to specific arginine residues of histones and nonhistone proteins. There are nine members in the PRMT family (PRMT1 to PRMT9), and PRMT1 is a dominant member catalyzing majority of arginine methylation in the cell. However, none of the PRMTs is active with recombinant nucleosome as substrate in vitro. Here, we report the discovery of the first in class novel crosstalk between histone H4 lysine 20 (H4K20) monomethylation on nucleosome by SETD8 and histone H4 arginine 3 (H4R3) methylation by PRMT1 in vitro. Full kinetic characterization and mass spectrometry analysis indicated that PRMT1 is only active with recombinant nucleosomes monomethylated at H4K20 by SETD8. These data suggests that the level of activity of PRMT1 could potentially be regulated selectively by SETD8 in various pathways, providing a new approach for discovery of selective regulators of PRMT1 activity.
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Affiliation(s)
- Alice Shi Ming Li
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada; Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada; Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada
| | - Charles Homsi
- Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montréal, Quebec H3C 3J7, Canada
| | - Eric Bonneil
- Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montréal, Quebec H3C 3J7, Canada
| | - Pierre Thibault
- Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montréal, Quebec H3C 3J7, Canada; Department of Chemistry, Université de Montréal, Montréal, Quebec H3C 3J7, Canada
| | - Alain Verreault
- Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montréal, Quebec H3C 3J7, Canada; Département de Pathologie et Biologie Cellulaire, Université de Montréal, QC, Canada
| | - Masoud Vedadi
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada; Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada; Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
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25
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Joseph FM, Young NL. Histone variant-specific post-translational modifications. Semin Cell Dev Biol 2023; 135:73-84. [PMID: 35277331 PMCID: PMC9458767 DOI: 10.1016/j.semcdb.2022.02.012] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 02/11/2022] [Accepted: 02/12/2022] [Indexed: 01/12/2023]
Abstract
Post-translational modifications (PTMs) of histones play a key role in DNA-based processes and contribute to cell differentiation and gene function by adding an extra layer of regulation. Variations in histone sequences within each family of histones expands the chromatin repertoire and provide further mechanisms for regulation and signaling. While variants are known to be present in certain genomic loci and carry out important functions, much remains unknown about variant-specific PTMs and their role in regulating chromatin. This ambiguity is in part due to the limited technologies and appropriate reagents to identify and quantitate variant-specific PTMs. Nonetheless, histone variants are an integral portion of the chromatin system and the understanding of their modifications and resolving how PTMs function differently on specific variants is paramount to the advancement of the field. Here we review the current knowledge on post-translational modifications specific to histone variants, with an emphasis on well-characterized PTMs of known function. While not every possible PTM is addressed, we present key variant-specific PTMs and what is known about their function and mechanisms in convenient reference tables.
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Affiliation(s)
- Faith M Joseph
- Translational Biology and Molecular Medicine Graduate Program, USA
| | - Nicolas L Young
- Translational Biology and Molecular Medicine Graduate Program, USA; Verna & Marrs McLean Department of Biochemistry & Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX 77030, USA.
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26
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Frigerio C, Di Nisio E, Galli M, Colombo CV, Negri R, Clerici M. The Chromatin Landscape around DNA Double-Strand Breaks in Yeast and Its Influence on DNA Repair Pathway Choice. Int J Mol Sci 2023; 24:ijms24043248. [PMID: 36834658 PMCID: PMC9967470 DOI: 10.3390/ijms24043248] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Revised: 01/21/2023] [Accepted: 02/01/2023] [Indexed: 02/09/2023] Open
Abstract
DNA double-strand breaks (DSBs) are harmful DNA lesions, which elicit catastrophic consequences for genome stability if not properly repaired. DSBs can be repaired by either non-homologous end joining (NHEJ) or homologous recombination (HR). The choice between these two pathways depends on which proteins bind to the DSB ends and how their action is regulated. NHEJ initiates with the binding of the Ku complex to the DNA ends, while HR is initiated by the nucleolytic degradation of the 5'-ended DNA strands, which requires several DNA nucleases/helicases and generates single-stranded DNA overhangs. DSB repair occurs within a precisely organized chromatin environment, where the DNA is wrapped around histone octamers to form the nucleosomes. Nucleosomes impose a barrier to the DNA end processing and repair machinery. Chromatin organization around a DSB is modified to allow proper DSB repair either by the removal of entire nucleosomes, thanks to the action of chromatin remodeling factors, or by post-translational modifications of histones, thus increasing chromatin flexibility and the accessibility of repair enzymes to the DNA. Here, we review histone post-translational modifications occurring around a DSB in the yeast Saccharomyces cerevisiae and their role in DSB repair, with particular attention to DSB repair pathway choice.
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Affiliation(s)
- Chiara Frigerio
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy
| | - Elena Di Nisio
- Department of Biology and Biotechnologies “C. Darwin”, Sapienza University of Rome, 00185 Rome, Italy
| | - Michela Galli
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy
| | - Chiara Vittoria Colombo
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy
| | - Rodolfo Negri
- Department of Biology and Biotechnologies “C. Darwin”, Sapienza University of Rome, 00185 Rome, Italy
- Institute of Molecular Biology and Pathology (IBPM), National Research Council (CNR) of Italy, 00185 Rome, Italy
- Correspondence: (R.N.); (M.C.)
| | - Michela Clerici
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy
- Correspondence: (R.N.); (M.C.)
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27
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Abramson HN. Recent Advances in the Applications of Small Molecules in the Treatment of Multiple Myeloma. Int J Mol Sci 2023; 24:2645. [PMID: 36768967 PMCID: PMC9917049 DOI: 10.3390/ijms24032645] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 01/15/2023] [Accepted: 01/24/2023] [Indexed: 02/01/2023] Open
Abstract
Therapy for multiple myeloma (MM), a hematologic neoplasm of plasma cells, has undergone remarkable changes over the past 25 years. Small molecules (molecular weight of less than one kDa), together with newer immunotherapies that include monoclonal antibodies, antibody-drug conjugates, and most recently, chimeric antigen receptor (CAR) T-cells, have combined to double the disease's five-year survival rate to over 50% during the past few decades. Despite these advances, the disease is still considered incurable, and its treatment continues to pose substantial challenges, since therapeutic refractoriness and patient relapse are exceedingly common. This review focuses on the current pipeline, along with the contemporary roles and future prospects for small molecules in MM therapy. While small molecules offer prospective benefits in terms of oral bioavailability, cellular penetration, simplicity of preparation, and improved cost-benefit considerations, they also pose problems of toxicity due to off-target effects. Highlighted in the discussion are recent developments in the applications of alkylating agents, immunomodulators, proteasome inhibitors, apoptosis inducers, kinesin spindle protein inhibitors, blockers of nuclear transport, and drugs that affect various kinases involved in intracellular signaling pathways. Molecular and cellular targets are described for each class of agents in relation to their roles as drivers of MM.
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Affiliation(s)
- Hanley N Abramson
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48202, USA
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28
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Zannino L, Pagano A, Casali C, Oldani M, Balestrazzi A, Biggiogera M. Mercury chloride alters heterochromatin domain organization and nucleolar activity in mouse liver. Histochem Cell Biol 2023; 159:61-76. [PMID: 36136163 PMCID: PMC9899742 DOI: 10.1007/s00418-022-02151-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/06/2022] [Indexed: 02/07/2023]
Abstract
Mercury is a highly toxic element that induces severe alterations and a broad range of adverse effects on health. Its exposure is a global concern because it is widespread in the environment due to its multiple industrial, domestic, agricultural and medical usages. Among its various chemical forms, both humans and animals are mainly exposed to mercury chloride (HgCl2), methylmercury and elemental mercury. HgCl2 is metabolized primarily in the liver. We analysed the effects on the nuclear architecture of an increasing dosage of HgCl2 in mouse hepatocytes cell culture and in mouse liver, focusing specifically on the organization, on some epigenetic features of the heterochromatin domains and on the nucleolar morphology and activity. Through the combination of molecular and imaging approaches both at optical and electron microscopy, we show that mercury chloride induces modifications of the heterochromatin domains and a decrease of some histones post-translational modifications associated to heterochromatin. This is accompanied by an increase in nucleolar activity which is reflected by bigger nucleoli. We hypothesized that heterochromatin decondensation and nucleolar activation following mercury chloride exposure could be functional to express proteins necessary to counteract the harmful stimulus and reach a new equilibrium.
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Affiliation(s)
- Lorena Zannino
- Department of Biology and Biotechnology ‘L. Spallanzani’, University of Pavia, 27100 Pavia, Italy
| | - Andrea Pagano
- Department of Biology and Biotechnology ‘L. Spallanzani’, University of Pavia, 27100 Pavia, Italy
| | - Claudio Casali
- Department of Biology and Biotechnology ‘L. Spallanzani’, University of Pavia, 27100 Pavia, Italy
| | - Monica Oldani
- Department of Biology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy
| | - Alma Balestrazzi
- Department of Biology and Biotechnology ‘L. Spallanzani’, University of Pavia, 27100 Pavia, Italy
| | - Marco Biggiogera
- Department of Biology and Biotechnology ‘L. Spallanzani’, University of Pavia, 27100 Pavia, Italy
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29
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Hou J, Dai J, Chen Z, Wang Y, Cao J, Hu J, Ye S, Hua Y, Zhao Y. Phosphorylation Regulation of a Histone-like HU Protein from Deinococcus radiodurans. Protein Pept Lett 2022; 29:891-899. [PMID: 35986527 PMCID: PMC9900698 DOI: 10.2174/0929866529666220819121911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 05/27/2022] [Accepted: 06/01/2022] [Indexed: 11/22/2022]
Abstract
BACKGROUND Histone-like proteins are small molecular weight DNA-binding proteins that are widely distributed in prokaryotes. These proteins have multiple functions in cellular structures and processes, including the morphological stability of the nucleoid, DNA compactness, DNA replication, and DNA repair. Deinococcus radiodurans, an extremophilic microorganism, has extraordinary DNA repair capability and encodes an essential histone-like protein, DrHU. OBJECTIVE We aim to investigate the phosphorylation regulation role of a histone-like HU protein from Deinococcus radiodurans. METHODS LC-MS/MS analysis was used to determine the phosphorylation site of endogenous DrHU. The predicted structure of DrHU-DNA was obtained from homology modeling (Swissmodel) using Staphylococcus aureus HU-DNA structure (PDB ID: 4QJU) as the starting model. Two types of mutant proteins T37E and T37A were generated to explore their DNA binding affinity. Complemented-knockout strategy was used to generate the ΔDrHU/pk-T37A and ΔDrHU/pk-T37E strains for growth curves and phenotypical analyses. RESULTS AND DISCUSSION The phosphorylation site Thr37, which is present in most bacterial HU proteins, is located at the putative protein-DNA interaction interface of DrHU. Compared to the wild-type protein, one in which this threonine is replaced by glutamate to mimic a permanent state of phosphorylation (T37E) showed enhanced double-stranded DNA binding but a weakened protective effect against hydroxyl radical cleavage. Complementation of T37E in a DrHU-knockout strain caused growth defects and sensitized the cells to UV radiation and oxidative stress. CONCLUSIONS Phosphorylation modulates the DNA-binding capabilities of the histone-like HU protein from D. radiodurans, which contributes to the environmental adaptation of this organism.
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Affiliation(s)
- Jinfeng Hou
- MOE Key Laboratory of Biosystems Homeostasis & Protection, College of Life Sciences, Zhejiang University, Hangzhou 310000, China
| | - Jingli Dai
- MOE Key Laboratory of Biosystems Homeostasis & Protection, College of Life Sciences, Zhejiang University, Hangzhou 310000, China
| | - Zijing Chen
- MOE Key Laboratory of Biosystems Homeostasis & Protection, College of Life Sciences, Zhejiang University, Hangzhou 310000, China
| | - Yudong Wang
- MOE Key Laboratory of Biosystems Homeostasis & Protection, College of Life Sciences, Zhejiang University, Hangzhou 310000, China
| | - Jiajia Cao
- MOE Key Laboratory of Biosystems Homeostasis & Protection, College of Life Sciences, Zhejiang University, Hangzhou 310000, China
| | - Jing Hu
- MOE Key Laboratory of Biosystems Homeostasis & Protection, College of Life Sciences, Zhejiang University, Hangzhou 310000, China
| | - Shumai Ye
- MOE Key Laboratory of Biosystems Homeostasis & Protection, College of Life Sciences, Zhejiang University, Hangzhou 310000, China
| | - Yuejin Hua
- MOE Key Laboratory of Biosystems Homeostasis & Protection, College of Life Sciences, Zhejiang University, Hangzhou 310000, China
| | - Ye Zhao
- MOE Key Laboratory of Biosystems Homeostasis & Protection, College of Life Sciences, Zhejiang University, Hangzhou 310000, China,Address correspondence to this author at the MOE Key Laboratory of Biosystems Homeostasis & Protection, College of Life Sciences, Zhejiang University, Hangzhou 310000, China; E-mail:
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30
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Gu Z, Chen X, Zhu D, Wu S, Yu C. Histone deacetylase 1 and 3 inhibitors alleviate colon inflammation by inhibiting Th17 cell differentiation. J Clin Lab Anal 2022; 36:e24699. [PMID: 36106389 PMCID: PMC9550981 DOI: 10.1002/jcla.24699] [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: 03/12/2022] [Revised: 06/25/2022] [Accepted: 07/19/2022] [Indexed: 11/20/2022] Open
Abstract
Background The etiology of inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is not completely clear, but its pathogenesis is closely related to T helper 17 (Th17) cells. Several histone deacetylase (HDAC) inhibitors have been shown to exert potent anti‐inflammatory effects and modulate Th17 cell polarization. Owing to the large variety and broad expression of HDACs, finding specific therapeutic targets for IBD is of clinical importance. Methods The proportions of Th17 cells and interleukin (IL)‐17A produced between patients with UC and healthy volunteers were compared. The differentiation of human peripheral blood mononuclear cells (PBMCs) into Th17 cells was induced in vitro. Differentiated Th17 cells were treated with RGFP109 (RG), a selective inhibitor of HDAC1 and 3, to observe its effects on these cells. Subsequently, colitis was induced in mice and treated with RG. The proportion of Th17 cells, the severity of colitis in mice, and colon histopathology and immunohistochemistry were evaluated respectively. Results The proportion of Th17 cells and IL‐17A production was significantly increased in patients with UC than in healthy individuals. RG inhibited the differentiation of human PBMCs into Th17 cells and reduced IL‐17A secretion in vitro. RG‐treated colitis mice had a lower Th17 ratio, mild colon inflammation, and decreased expression of HDAC1 and 3 in the colon. Conclusions HDAC1 and 3 inhibitors can modulate the differentiation of inflammatory Th17 cells, downregulate IL‐17A levels, and exert anti‐inflammatory effects in experimental colitis mice, indicating that HDAC1 and 3 may be potential therapeutic targets for patients with IBD.
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Affiliation(s)
- Zhengrong Gu
- Department of Gastroenterology, Nanjing Drum Tower Hospital The Affiliated Hospital of Nanjing University Medical School Nanjing China
| | - Xiaotian Chen
- Department of Clinical Nutrition, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University Nanjing China
| | - Dandan Zhu
- Department of Gastroenterology, Nanjing Drum Tower Hospital The Affiliated Hospital of Nanjing University Medical School Nanjing China
| | - Songting Wu
- Department of Gastroenterology, Nanjing Drum Tower Hospital The Affiliated Hospital of Nanjing University Medical School Nanjing China
| | - Chenggong Yu
- Department of Gastroenterology, Nanjing Drum Tower Hospital The Affiliated Hospital of Nanjing University Medical School Nanjing China
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31
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Shrestha S, Lucky AB, Brashear AM, Li X, Cui L, Miao J. Distinct Histone Post-translational Modifications during Plasmodium falciparum Gametocyte Development. J Proteome Res 2022; 21:1857-1867. [PMID: 35772009 PMCID: PMC9738646 DOI: 10.1021/acs.jproteome.2c00108] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Histones are the building units of nucleosomes, which constitute chromatin. Histone post-translational modifications (PTMs) play an essential role in epigenetic gene regulation. The Plasmodium falciparum genome encodes canonical and variant histones and a collection of conserved enzymes for histone PTMs and chromatin remodeling. Herein, we profiled the P. falciparum histone PTMs during the development of gametocytes, the obligatory stage for parasite transmission. Mass spectrometric analysis of histones extracted from the early, middle, and late stages of gametocytes identified 457 unique histone peptides with 90 PTMs, of which 50% were novel. The gametocyte histone PTMs display distinct patterns from asexual stages, with many new methylation sites in histones H3 and H3.3 (e.g., K14, K18, and K37). Quantitative analyses revealed a high abundance of acetylation in H3 and H4, mono-methylation of H3/H3.3 K37, and ubiquitination of H3BK112, suggesting that these PTMs play critical roles in gametocytes. Gametocyte histones also showed extensive and unique combinations of PTMs. These data indicate that the parasite harbors distinct transcription regulation mechanisms during gametocyte development and lay the foundation for further characterization of epigenetic regulation in the life cycle of the malaria parasite.
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Affiliation(s)
- Sony Shrestha
- Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, United States
| | - Amuza Byaruhanga Lucky
- Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, United States
| | - Awtum Marie Brashear
- Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, United States
| | - Xiaolian Li
- Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, United States
| | - Liwang Cui
- Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, United States; Center for Global Health and Infectious Diseases Research, College of Public Health, University of South Florida, Tampa, Florida 33612, United States
| | - Jun Miao
- Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, United States; Center for Global Health and Infectious Diseases Research, College of Public Health, University of South Florida, Tampa, Florida 33612, United States
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32
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Biechele-Speziale DJ, Sutton TB, Delaney S. Obstacles and opportunities for base excision repair in chromatin. DNA Repair (Amst) 2022; 116:103345. [PMID: 35689883 PMCID: PMC9253077 DOI: 10.1016/j.dnarep.2022.103345] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 05/20/2022] [Accepted: 05/24/2022] [Indexed: 01/01/2023]
Abstract
Most eukaryotic DNA is packaged into chromatin, which is made up of tandemly repeating nucleosomes. This packaging of DNA poses a significant barrier to the various enzymes that must act on DNA, including DNA damage response enzymes that interact intimately with DNA to prevent mutations and cell death. To regulate access to certain DNA regions, chromatin remodeling, variant histone exchange, and histone post-translational modifications have been shown to assist several DNA repair pathways including nucleotide excision repair, single strand break repair, and double strand break repair. While these chromatin-level responses have been directly linked to various DNA repair pathways, how they modulate the base excision repair (BER) pathway remains elusive. This review highlights recent findings that demonstrate how BER is regulated by the packaging of DNA into nucleosome core particles (NCPs) and higher orders of chromatin structures. We also summarize the available data that indicate BER may be enabled by chromatin modifications and remodeling.
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Affiliation(s)
| | | | - Sarah Delaney
- Department of Chemistry, Brown University, Providence, RI, USA.
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33
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Tsunaka Y, Furukawa A, Nishimura Y. Histone tail network and modulation in a nucleosome. Curr Opin Struct Biol 2022; 75:102436. [PMID: 35863166 DOI: 10.1016/j.sbi.2022.102436] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 06/17/2022] [Accepted: 06/17/2022] [Indexed: 11/18/2022]
Abstract
The structural unit of eukaryotic chromatin is a nucleosome, comprising two histone H2A/H2B heterodimers and one histone (H3/H4)2 tetramer, wrapped around by ∼146-bp core DNA and linker DNA. Flexible histone tails sticking out from the core undergo posttranslational modifications that are responsible for various epigenetic functions. Recently, the functional dynamics of histone tails and their modulation within the nucleosome and nucleosomal complexes have been investigated by integrating NMR, molecular dynamics simulations, and cryo-electron microscopy approaches. In particular, recent NMR studies have revealed correlations in the structures of histone N-terminal tails between H2A and H2B, as well as between H3 and H4 depending on linker DNA, suggesting that histone tail networks exist even within the nucleosome.
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Affiliation(s)
- Yasuo Tsunaka
- Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan
| | - Ayako Furukawa
- Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan
| | - Yoshifumi Nishimura
- Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan; Graduate School of Integrated Sciences for Life, Hiroshima University, 1-4-4 Kagamiyama, Higashi-Hiroshima 739-8528, Japan.
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34
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Czaja AJ. Epigenetic Aspects and Prospects in Autoimmune Hepatitis. Front Immunol 2022; 13:921765. [PMID: 35844554 PMCID: PMC9281562 DOI: 10.3389/fimmu.2022.921765] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Accepted: 05/12/2022] [Indexed: 12/12/2022] Open
Abstract
The observed risk of autoimmune hepatitis exceeds its genetic risk, and epigenetic factors that alter gene expression without changing nucleotide sequence may help explain the disparity. Key objectives of this review are to describe the epigenetic modifications that affect gene expression, discuss how they can affect autoimmune hepatitis, and indicate prospects for improved management. Multiple hypo-methylated genes have been described in the CD4+ and CD19+ T lymphocytes of patients with autoimmune hepatitis, and the circulating micro-ribonucleic acids, miR-21 and miR-122, have correlated with laboratory and histological features of liver inflammation. Both epigenetic agents have also correlated inversely with the stage of liver fibrosis. The reduced hepatic concentration of miR-122 in cirrhosis suggests that its deficiency may de-repress the pro-fibrotic prolyl-4-hydroxylase subunit alpha-1 gene. Conversely, miR-155 is over-expressed in the liver tissue of patients with autoimmune hepatitis, and it may signify active immune-mediated liver injury. Different epigenetic findings have been described in diverse autoimmune and non-autoimmune liver diseases, and these changes may have disease-specificity. They may also be responses to environmental cues or heritable adaptations that distinguish the diseases. Advances in epigenetic editing and methods for blocking micro-ribonucleic acids have improved opportunities to prove causality and develop site-specific, therapeutic interventions. In conclusion, the role of epigenetics in affecting the risk, clinical phenotype, and outcome of autoimmune hepatitis is under-evaluated. Full definition of the epigenome of autoimmune hepatitis promises to enhance understanding of pathogenic mechanisms and satisfy the unmet clinical need to improve therapy for refractory disease.
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Affiliation(s)
- Albert J. Czaja
- *Correspondence: Albert J. Czaja, ; orcid.org/0000-0002-5024-3065
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Nevedomskaya E, Haendler B. From Omics to Multi-Omics Approaches for In-Depth Analysis of the Molecular Mechanisms of Prostate Cancer. Int J Mol Sci 2022; 23:6281. [PMID: 35682963 PMCID: PMC9181488 DOI: 10.3390/ijms23116281] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 05/24/2022] [Accepted: 06/01/2022] [Indexed: 02/01/2023] Open
Abstract
Cancer arises following alterations at different cellular levels, including genetic and epigenetic modifications, transcription and translation dysregulation, as well as metabolic variations. High-throughput omics technologies that allow one to identify and quantify processes involved in these changes are now available and have been instrumental in generating a wealth of steadily increasing data from patient tumors, liquid biopsies, and from tumor models. Extensive investigation and integration of these data have led to new biological insights into the origin and development of multiple cancer types and helped to unravel the molecular networks underlying this complex pathology. The comprehensive and quantitative analysis of a molecule class in a biological sample is named omics and large-scale omics studies addressing different prostate cancer stages have been performed in recent years. Prostate tumors represent the second leading cancer type and a prevalent cause of cancer death in men worldwide. It is a very heterogenous disease so that evaluating inter- and intra-tumor differences will be essential for a precise insight into disease development and plasticity, but also for the development of personalized therapies. There is ample evidence for the key role of the androgen receptor, a steroid hormone-activated transcription factor, in driving early and late stages of the disease, and this led to the development and approval of drugs addressing diverse targets along this pathway. Early genomic and transcriptomic studies have allowed one to determine the genes involved in prostate cancer and regulated by androgen signaling or other tumor-relevant signaling pathways. More recently, they have been supplemented by epigenomic, cistromic, proteomic and metabolomic analyses, thus, increasing our knowledge on the intricate mechanisms involved, the various levels of regulation and their interplay. The comprehensive investigation of these omics approaches and their integration into multi-omics analyses have led to a much deeper understanding of the molecular pathways involved in prostate cancer progression, and in response and resistance to therapies. This brings the hope that novel vulnerabilities will be identified, that existing therapies will be more beneficial by targeting the patient population likely to respond best, and that bespoke treatments with increased efficacy will be available soon.
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Affiliation(s)
| | - Bernard Haendler
- Research and Early Development, Pharmaceuticals, Bayer AG, Müllerstr. 178, 13353 Berlin, Germany;
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Tabassum Z, Tseng JH, Isemann C, Tian X, Chen Y, Herring LE, Cohen TJ. Identification of a reciprocal negative feedback loop between tau-modifying proteins MARK2 kinase and CBP acetyltransferase. J Biol Chem 2022; 298:101977. [PMID: 35469920 PMCID: PMC9136110 DOI: 10.1016/j.jbc.2022.101977] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Revised: 04/14/2022] [Accepted: 04/16/2022] [Indexed: 11/30/2022] Open
Abstract
The posttranslational regulation of the neuronal proteome is critical for brain homeostasis but becomes dysregulated in the aged or diseased brain, in which abnormal posttranslational modifications (PTMs) are frequently observed. While the full extent of modified substrates that comprise the "PTM-ome" are slowly emerging, how the upstream enzymes catalyzing these processes are regulated themselves is not well understood, particularly in the context of neurodegeneration. Here, we describe the reciprocal regulation of a kinase, the microtubule affinity-regulating kinase 2 (MARK2), and an acetyltransferase, CREB-binding protein (CBP), two enzymes known to extensively modify tau proteins in the progression of Alzheimer's disease. We found that MARK2 negatively regulates CBP and, conversely, CBP directly acetylates and inhibits MARK2 kinase activity. These findings highlight a reciprocal negative feedback loop between a kinase and an acetyltransferase, which has implications for how PTM interplay is coordinated on substrates including tau. Our study suggests that PTM profiles occur through the posttranslational control of the master PTM remodeling enzymes themselves.
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Affiliation(s)
- Zarin Tabassum
- Department of Neurology, UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Jui-Heng Tseng
- Department of Neurology, UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Camryn Isemann
- Department of Neurology, UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Xu Tian
- Department of Neurology, UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Youjun Chen
- Department of Neurology, UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Laura E Herring
- UNC Proteomics Core Facility, Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Todd J Cohen
- Department of Neurology, UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina, USA.
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High-throughput profiling of histone post-translational modifications and chromatin modifying proteins by reverse phase protein array. J Proteomics 2022; 262:104596. [PMID: 35489683 PMCID: PMC10165948 DOI: 10.1016/j.jprot.2022.104596] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 03/23/2022] [Accepted: 04/11/2022] [Indexed: 11/22/2022]
Abstract
Epigenetic variation plays a significant role in normal development and human diseases including cancer, in part through post-translational modifications (PTMs) of histones. Identification and profiling of changes in histone PTMs, and in proteins regulating PTMs, are crucial to understanding diseases, and for discovery of epigenetic therapeutic agents. In this study, we have adapted and validated an antibody-based reverse phase protein array (RPPA) platform for profiling 20 histone PTMs and expression of 40 proteins that modify histones and other epigenomic regulators. The specificity of the RPPA assay for histone PTMs was validated with synthetic peptides corresponding to histone PTMs and by detection of histone PTM changes in response to inhibitors of histone modifier proteins in cell cultures. The useful application of the RPPA platform was demonstrated with two models: induction of pluripotent stem cells and a mouse mammary tumor progression model. Described here is a robust platform that includes a rapid microscale method for histone isolation and partially automated workflows for analysis of histone PTMs and histone modifiers that can be performed in a high-throughput manner with hundreds of samples. This RPPA platform has potential for translational applications through the discovery and validation of epigenetic states as therapeutic targets and biomarkers. SIGNIFICANCE: Our study has established an antibody-based reverse phase protein array platform for global profiling of a wide range of post-translational modifications of histones and histone modifier proteins. The high-throughput platform provides comprehensive analyses of epigenetics for biological research and disease studies and may serve as screening assay for diagnostic purpose or therapy development.
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Sobering AK, Bryant LM, Li D, McGaughran J, Maystadt I, Moortgat S, Graham JM, van Haeringen A, Ruivenkamp C, Cuperus R, Vogt J, Morton J, Brasch-Andersen C, Steenhof M, Hansen LK, Adler É, Lyonnet S, Pingault V, Sandrine M, Ziegler A, Donald T, Nelson B, Holt B, Petryna O, Firth H, McWalter K, Zyskind J, Telegrafi A, Juusola J, Person R, Bamshad MJ, Earl D, Tsai ACH, Yearwood KR, Marco E, Nowak C, Douglas J, Hakonarson H, Bhoj EJ. Variants in PHF8 cause a spectrum of X-linked neurodevelopmental disorders and facial dysmorphology. HGG ADVANCES 2022; 3:100102. [PMID: 35469323 PMCID: PMC9034099 DOI: 10.1016/j.xhgg.2022.100102] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 03/18/2022] [Indexed: 01/25/2023] Open
Abstract
Loss-of-function variants in PHD Finger Protein 8 (PHF8) cause Siderius X-linked intellectual disability (ID) syndrome, hereafter called PHF8-XLID. PHF8 is a histone demethylase that is important for epigenetic regulation of gene expression. PHF8-XLID is an under-characterized disorder with only five previous reports describing different PHF8 predicted loss-of-function variants in eight individuals. Features of PHF8-XLID include ID and craniofacial dysmorphology. In this report we present 16 additional individuals with PHF8-XLID from 11 different families of diverse ancestry. We also present five individuals from four different families who have ID and a variant of unknown significance in PHF8 with no other explanatory variant in another gene. All affected individuals exhibited developmental delay and all but two had borderline to severe ID. Of the two who did not have ID, one had dyscalculia and the other had mild learning difficulties. Craniofacial findings such as hypertelorism, microcephaly, elongated face, ptosis, and mild facial asymmetry were found in some affected individuals. Orofacial clefting was seen in three individuals from our cohort, suggesting that this feature is less common than previously reported. Autism spectrum disorder and attention deficit hyperactivity disorder, which were not previously emphasized in PHF8-XLID, were frequently observed in affected individuals. This series expands the clinical phenotype of this rare ID syndrome caused by loss of PHF8 function.
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Affiliation(s)
- Andrew K. Sobering
- AU/UGA Medical Partnership, Department of Basic Sciences, University of Georgia Health Sciences Campus, Athens, GA 30602, USA
- St. George’s University, Department of Biochemistry, St. George’s, Grenada, West Indies
- Windward Islands Research and Education Foundation, True Blue, St. George’s, Grenada, West Indies
- Corresponding author
| | - Laura M. Bryant
- Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Dong Li
- Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Julie McGaughran
- Genetic Health Queensland, RBWH, Brisbane and The University of Queensland School of Medicine, Brisbane, QLD 4029, Australia
| | - Isabelle Maystadt
- Centre de Génétique Humaine, Institut de Pathologie et de Génétique, 6041 Gosselies, Belgium
| | - Stephanie Moortgat
- Centre de Génétique Humaine, Institut de Pathologie et de Génétique, 6041 Gosselies, Belgium
| | - John M. Graham
- Medical Genetics, Department of Pediatrics, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA 90048, USA
| | | | | | - Roos Cuperus
- Juliana Children’s Hospital, HAGA Medical Center, The Hague, the Netherlands
| | - Julie Vogt
- Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham Women’s Hospital, Birmingham B15 2TG, UK
| | - Jenny Morton
- West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women’s Hospital NHS Foundation Trust, Birmingham B15 2TG, UK
| | - Charlotte Brasch-Andersen
- Department of Clinical Genetics, Odense University Hospital, Odense 5000, Denmark
- Human Genetics, Department of Clinical Research, University of Southern Denmark, Odense 5000, Denmark
| | - Maria Steenhof
- Department of Clinical Genetics, Odense University Hospital, Odense 5000, Denmark
| | | | - Élodie Adler
- Fédération de Médecine Génomique and Imagine Institute, Université de Paris, Hôpital Necker-Enfants Malades, APHP, 75015 Paris, France
| | - Stanislas Lyonnet
- Fédération de Médecine Génomique and Imagine Institute, Université de Paris, Hôpital Necker-Enfants Malades, APHP, 75015 Paris, France
| | - Veronique Pingault
- Fédération de Médecine Génomique and Imagine Institute, Université de Paris, Hôpital Necker-Enfants Malades, APHP, 75015 Paris, France
| | - Marlin Sandrine
- Reference Center for Genetic Deafness, Fédération de Médecine Génomique and Imagine Institute, Université de Paris, Hôpital Necker-Enfants Malades, APHP, 75015 Paris, France
| | - Alban Ziegler
- Reference Center for Genetic Deafness, Fédération de Médecine Génomique and Imagine Institute, Université de Paris, Hôpital Necker-Enfants Malades, APHP, 75015 Paris, France
| | - Tyhiesia Donald
- Clinical Teaching Unit, St. George’s University School of Medicine, St. George’s, Grenada, West Indies
| | - Beverly Nelson
- Clinical Teaching Unit, St. George’s University School of Medicine, St. George’s, Grenada, West Indies
| | - Brandon Holt
- Department of Anatomical Sciences, St. George’s University, Grenada, West Indies
| | - Oleksandra Petryna
- Hackensack University Ocean Medical Center, Department of Psychiatry, Hackensack, NJ 08724, USA
| | - Helen Firth
- Department of Clinical Genetics, Cambridge University Hospitals, Box 134, Cambridge CB2 0QQ, UK
| | | | - Jacob Zyskind
- Clinical Genomics, GeneDx, Gaithersburg, MD 20877, USA
| | | | - Jane Juusola
- Clinical Genomics, GeneDx, Gaithersburg, MD 20877, USA
| | | | - Michael J. Bamshad
- Seattle Children’s Hospital, Seattle, WA 98105, USA
- Departments of Pediatrics and Genome Sciences, University of Washington, Seattle, WA 98195, USA
- Brotman-Baty Institute, Seattle, WA 98195, USA
| | - Dawn Earl
- Seattle Children’s Hospital, Seattle, WA 98105, USA
| | | | - Anne Chun-Hui Tsai
- University of Oklahoma, Section of Genetics, 800 Stanton L Young Boulevard, Oklahoma City, OK 73117, USA
| | | | - Elysa Marco
- Cortica Healthcare, Marin Center, 4000 Civic Center Dr, Ste 100, San Rafael, CA 94903, USA
| | - Catherine Nowak
- Boston Children’s Hospital, Division of Genetics and Genomics, 60 Temple Place, 2nd Floor, Boston, MA 02111, USA
| | - Jessica Douglas
- Boston Children’s Hospital, Division of Genetics and Genomics, 60 Temple Place, 2nd Floor, Boston, MA 02111, USA
| | - Hakon Hakonarson
- Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Division of Human Genetics, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Elizabeth J. Bhoj
- Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Division of Human Genetics, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
- Corresponding author
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Nilsson EE, Ben Maamar M, Skinner MK. Role of epigenetic transgenerational inheritance in generational toxicology. ENVIRONMENTAL EPIGENETICS 2022; 8:dvac001. [PMID: 35186326 PMCID: PMC8848501 DOI: 10.1093/eep/dvac001] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 11/04/2021] [Accepted: 02/03/2022] [Indexed: 05/27/2023]
Abstract
Many environmental toxicants have been shown to be associated with the transgenerational inheritance of increased disease susceptibility. This review describes the generational toxicity of some of these chemicals and their role in the induction of epigenetic transgenerational inheritance of disease. Epigenetic factors include DNA methylation, histone modifications, retention of histones in sperm, changes to chromatin structure, and expression of non-coding RNAs. For toxicant-induced epigenetic transgenerational inheritance to occur, exposure to a toxicant must result in epigenetic changes to germ cells (sperm or eggs) since it is the germ cells that carry molecular information to subsequent generations. In addition, the epigenetic changes induced in transgenerational generation animals must cause alterations in gene expression in these animals' somatic cells. In some cases of generational toxicology, negligible changes are seen in the directly exposed generations, but increased disease rates are seen in transgenerational descendants. Governmental policies regulating toxicant exposure should take generational effects into account. A new approach that takes into consideration generational toxicity will be needed to protect our future populations.
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Affiliation(s)
- Eric E Nilsson
- Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, WA 99164-4236, USA
| | - Millissia Ben Maamar
- Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, WA 99164-4236, USA
| | - Michael K Skinner
- **Correspondence address. Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, WA 99164-4236, USA. Tel: +509-335-1524; E-mail:
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40
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Verhelst S, Van Puyvelde B, Willems S, Daled S, Cornelis S, Corveleyn L, Willems E, Deforce D, De Clerck L, Dhaenens M. A large scale mass spectrometry-based histone screening for assessing epigenetic developmental toxicity. Sci Rep 2022; 12:1256. [PMID: 35075221 PMCID: PMC8786925 DOI: 10.1038/s41598-022-05268-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 01/07/2022] [Indexed: 12/23/2022] Open
Abstract
Toxicoepigenetics is an emerging field that studies the toxicological impact of compounds on protein expression through heritable, non-genetic mechanisms, such as histone post-translational modifications (hPTMs). Due to substantial progress in the large-scale study of hPTMs, integration into the field of toxicology is promising and offers the opportunity to gain novel insights into toxicological phenomena. Moreover, there is a growing demand for high-throughput human-based in vitro assays for toxicity testing, especially for developmental toxicity. Consequently, we developed a mass spectrometry-based proof-of-concept to assess a histone code screening assay capable of simultaneously detecting multiple hPTM-changes in human embryonic stem cells. We first validated the untargeted workflow with valproic acid (VPA), a histone deacetylase inhibitor. These results demonstrate the capability of mapping the hPTM-dynamics, with a general increase in acetylations as an internal control. To illustrate the scalability, a dose–response study was performed on a proof-of-concept library of ten compounds (1) with a known effect on the hPTMs (BIX-01294, 3-Deazaneplanocin A, Trichostatin A, and VPA), (2) classified as highly embryotoxic by the European Centre for the Validation of Alternative Methods (ECVAM) (Methotrexate, and All-trans retinoic acid), (3) classified as non-embryotoxic by ECVAM (Penicillin G), and (4) compounds of abuse with a presumed developmental toxicity (ethanol, caffeine, and nicotine).
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Affiliation(s)
- Sigrid Verhelst
- ProGenTomics, Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium
| | - Bart Van Puyvelde
- ProGenTomics, Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium
| | - Sander Willems
- Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, 82152, Martinsried, Germany
| | - Simon Daled
- ProGenTomics, Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium
| | - Senne Cornelis
- ProGenTomics, Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium
| | - Laura Corveleyn
- ProGenTomics, Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium
| | - Ewoud Willems
- ProGenTomics, Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium
| | - Dieter Deforce
- ProGenTomics, Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium
| | - Laura De Clerck
- ProGenTomics, Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium
| | - Maarten Dhaenens
- ProGenTomics, Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium.
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Kanapeckaitė A, Burokienė N, Mažeikienė A, Cottrell GS, Widera D. Biophysics is reshaping our perception of the epigenome: from DNA-level to high-throughput studies. BIOPHYSICAL REPORTS 2021; 1:100028. [PMID: 36425454 PMCID: PMC9680810 DOI: 10.1016/j.bpr.2021.100028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 09/24/2021] [Indexed: 06/16/2023]
Abstract
Epigenetic research holds great promise to advance our understanding of biomarkers and regulatory processes in health and disease. An increasing number of new approaches, ranging from molecular to biophysical analyses, enable identifying epigenetic changes on the level of a single gene or the whole epigenome. The aim of this review is to highlight how the field is shifting from completely molecular-biology-driven solutions to multidisciplinary strategies including more reliance on biophysical analysis tools. Biophysics not only offers technical advancements in imaging or structure analysis but also helps to explore regulatory interactions. New computational methods are also being developed to meet the demand of growing data volumes and their processing. Therefore, it is important to capture these new directions in epigenetics from a biophysical perspective and discuss current challenges as well as multiple applications of biophysical methods and tools. Specifically, we gradually introduce different biophysical research methods by first considering the DNA-level information and eventually higher-order chromatin structures. Moreover, we aim to highlight that the incorporation of bioinformatics, machine learning, and artificial intelligence into biophysical analysis allows gaining new insights into complex epigenetic processes. The gained understanding has already proven useful in translational and clinical research providing better patient stratification options or new therapeutic insights. Together, this offers a better readiness to transform bench-top experiments into industrial high-throughput applications with a possibility to employ developed methods in clinical practice and diagnostics.
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Affiliation(s)
- Austė Kanapeckaitė
- Algorithm379, Laisvės g. 7, LT 12007, Vilnius, Lithuania
- Reading School of Pharmacy, Whiteknights, Reading, UK, RG6 6UB
| | - Neringa Burokienė
- Clinics of Internal Diseases, Family Medicine and Oncology, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, M. K. Čiurlionio str. 21/27, LT-03101 Vilnius, Lithuania
| | - Asta Mažeikienė
- Department of Physiology, Biochemistry, Microbiology and Laboratory Medicine, Institute of Biomedical Sciences, Faculty of Medicine, M. K. Čiurlionio str. 21/27, LT-03101 Vilnius, Lithuania
| | | | - Darius Widera
- Reading School of Pharmacy, Whiteknights, Reading, UK, RG6 6UB
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Kennedy PGE, Mogensen TH, Cohrs RJ. Recent Issues in Varicella-Zoster Virus Latency. Viruses 2021; 13:v13102018. [PMID: 34696448 PMCID: PMC8540691 DOI: 10.3390/v13102018] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 09/30/2021] [Accepted: 10/02/2021] [Indexed: 12/16/2022] Open
Abstract
Varicella-zoster virus (VZV) is a human herpes virus which causes varicella (chicken pox) as a primary infection, and, following a variable period of latency in neurons in the peripheral ganglia, may reactivate to cause herpes zoster (shingles) as well as a variety of neurological syndromes. In this overview we consider some recent issues in alphaherpesvirus latency with special focus on VZV ganglionic latency. A key question is the nature and extent of viral gene transcription during viral latency. While it is known that this is highly restricted, it is only recently that the very high degree of that restriction has been clarified, with both VZV gene 63-encoded transcripts and discovery of a novel VZV transcript (VLT) that maps antisense to the viral transactivator gene 61. It has also emerged in recent years that there is significant epigenetic regulation of VZV gene transcription, and the mechanisms underlying this are complex and being unraveled. The last few years has also seen an increased interest in the immunological aspects of VZV latency and reactivation, in particular from the perspective of inborn errors of host immunity that predispose to different VZV reactivation syndromes.
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Affiliation(s)
- Peter G. E. Kennedy
- Institute of Neuroscience and Psychology, University of Glasgow, Glasgow G61 1QH, UK
- Correspondence:
| | - Trine H. Mogensen
- Department of Infectious Diseases, Aarhus University Hospital, 8000 Aarhus, Denmark;
- Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark
| | - Randall J. Cohrs
- Department of Neurology, University of Colorado School of Medicine, 80045 Aurora, CO, USA
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Zurek M, Aavik E, Mallick R, Ylä-Herttuala S. Epigenetic Regulation of Vascular Smooth Muscle Cell Phenotype Switching in Atherosclerotic Artery Remodeling: A Mini-Review. Front Genet 2021; 12:719456. [PMID: 34422021 PMCID: PMC8375552 DOI: 10.3389/fgene.2021.719456] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 07/19/2021] [Indexed: 12/11/2022] Open
Abstract
Atherosclerosis is a chronic inflammatory disease characterized by extensive remodeling of medium and large-sized arteries. Inward remodeling (=lumen shrinkage) of the vascular walls is the underlying cause for ischemia in target organs. Therefore, inward remodeling can be considered the predominant feature of atherosclerotic pathology. Outward remodeling (=lumen enlargement) is a physiological response compensating for lumen shrinkage caused by neointimal hyperplasia, but as a pathological response to changes in blood flow, outward remodeling leads to substantial arterial wall thinning. Thinned vascular walls are prone to rupture, and subsequent thrombus formation accounts for the majority of acute cardiovascular events. Pathological remodeling is driven by inflammatory cells which induce vascular smooth muscle cells to switch from quiescent to a proliferative and migratory phenotype. After decades of intensive research, the molecular mechanisms of arterial remodeling are starting to unfold. In this mini-review, we summarize the current knowledge of the epigenetic and transcriptional regulation of vascular smooth muscle cell phenotype switching from the contractile to the synthetic phenotype involved in arterial remodeling and discuss potential therapeutic options.
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Affiliation(s)
- Michelle Zurek
- A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
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Sun F, Suttapitugsakul S, Wu R. An Azo Coupling-Based Chemoproteomic Approach to Systematically Profile the Tyrosine Reactivity in the Human Proteome. Anal Chem 2021; 93:10334-10342. [PMID: 34251175 PMCID: PMC8525517 DOI: 10.1021/acs.analchem.1c01935] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
The tyrosine residue of proteins participates in a wide range of activities including enzymatic catalysis, protein-protein interaction, and protein-ligand binding. However, the functional annotation of the tyrosine residues on a large scale is still very challenging. Here, we report a novel method integrating azo coupling, bioorthogonal chemistry, and multiplexed proteomics to globally investigate the tyrosine reactivity in the human proteome. Based on the azo-coupling reaction between aryl diazonium salt and the tyrosine residue, two different probes were evaluated, and the probe with the best performance was employed to further study the tyrosine residues in the human proteome. Then, tagged tyrosine-containing peptides were selectively enriched using bioorthogonal chemistry, and after the cleavage, a small tag on the peptides perfectly fits for site-specific analysis by MS. Coupling with multiplexed proteomics, we quantified over 5000 tyrosine sites in MCF7 cells, and these quantified sites displayed a wide range of reactivity. The tyrosine residues with high reactivity were found on functionally and structurally diverse proteins, including those with the catalytic activity and binding property. This method can be extensively applied to advance our understanding of protein functions and facilitate the development of covalent drugs to regulate protein activity.
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Affiliation(s)
- Fangxu Sun
- School of Chemistry and Biochemistry and the Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
| | - Suttipong Suttapitugsakul
- School of Chemistry and Biochemistry and the Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
| | - Ronghu Wu
- School of Chemistry and Biochemistry and the Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
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Skinner MK, Nilsson EE. Role of environmentally induced epigenetic transgenerational inheritance in evolutionary biology: Unified Evolution Theory. ENVIRONMENTAL EPIGENETICS 2021; 7:dvab012. [PMID: 34729214 PMCID: PMC8557805 DOI: 10.1093/eep/dvab012] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 10/07/2021] [Accepted: 10/12/2021] [Indexed: 05/15/2023]
Abstract
The current evolutionary biology theory primarily involves genetic alterations and random DNA sequence mutations to generate the phenotypic variation required for Darwinian natural selection to act. This neo-Darwinian evolution is termed the Modern Evolution Synthesis and has been the primary paradigm for nearly 100 years. Although environmental factors have a role in neo-Darwinian natural selection, Modern Evolution Synthesis does not consider environment to impact the basic molecular processes involved in evolution. An Extended Evolutionary Synthesis has recently developed that extends the modern synthesis to consider non-genetic processes. Over the past few decades, environmental epigenetics research has been demonstrated to regulate genetic processes and directly generate phenotypic variation independent of genetic sequence alterations. Therefore, the environment can on a molecular level through non-genetic (i.e. epigenetic) mechanisms directly influence phenotypic variation, genetic variation, inheritance and adaptation. This direct action of the environment to alter phenotype that is heritable is a neo-Lamarckian concept that can facilitate neo-Darwinian (i.e. Modern Synthesis) evolution. The integration of genetics, epigenetics, Darwinian theory, Lamarckian concepts, environment, and epigenetic inheritance provides a paradigm shift in evolution theory. The role of environmental-induced epigenetic transgenerational inheritance in evolution is presented to describe a more unified theory of evolutionary biology.
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Affiliation(s)
- Michael K Skinner
- **Correspondence address. Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, WA 99164-4236, USA. Tel: +1 509-335-1524; E-mail:
| | - Eric E Nilsson
- Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, WA 99164-4236, USA
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