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Mao S, Song C, Huang H, Nie Y, Ding K, Cui J, Tian J, Tang H. Role of transcriptional cofactors in cardiovascular diseases. Biochem Biophys Res Commun 2024; 706:149757. [PMID: 38490050 DOI: 10.1016/j.bbrc.2024.149757] [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: 12/09/2023] [Revised: 02/16/2024] [Accepted: 03/04/2024] [Indexed: 03/17/2024]
Abstract
Cardiovascular disease is a main cause of mortality in the world and the highest incidence of all diseases. However, the mechanism of the pathogenesis of cardiovascular disease is still unclear, and we need to continue to explore its mechanism of action. The occurrence and development of cardiovascular disease is significantly associated with genetic abnormalities, and gene expression is affected by transcriptional regulation. In this complex process, the protein-protein interaction promotes the RNA polymerase II to the initiation site. And in this process of transcriptional regulation, transcriptional cofactors are responsible for passing cues from enhancers to promoters and promoting the binding of RNA polymerases to promoters, so transcription cofactors playing a key role in gene expression regulation. There is growing evidence that transcriptional cofactors play a critical role in cardiovascular disease. Transcriptional cofactors can promote or inhibit transcription by affecting the function of transcription factors. It can affect the initiation and elongation process of transcription by forming complexes with transcription factors, which are important for the stabilization of DNA rings. It can also act as a protein that interacts with other proteins to affect the expression of other genes. Therefore, the aim of this overview is to summarize the effect of some transcriptional cofactors such as BRD4, EP300, MED1, EZH2, YAP, SIRT6 in cardiovascular disease and to provide a promising therapeutic strategy for the treatment of cardiovascular disease.
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Affiliation(s)
- Shuqing Mao
- Hunan Provincial Key Laboratory of Multi-omics and Artificial Intelligence of Cardiovascular Diseases, University of South China, Hengyang, Hunan, 421001, China; The First Affiliated Hospital, Department of Cardiology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China; Clinical Research Center for Myocardial Injury in Hunan Province, Hengyang, Hunan, 421001, China; The First Affiliated Hospital, Institute of Cardiovascular Disease, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Chao Song
- Hunan Provincial Key Laboratory of Multi-omics and Artificial Intelligence of Cardiovascular Diseases, University of South China, Hengyang, Hunan, 421001, China; The First Affiliated Hospital, Institute of Cardiovascular Disease, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China; The First Affiliated Hospital, Cardiovascular Lab of Big Data and Imaging Artificial Intelligence, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Hong Huang
- Hunan Provincial Key Laboratory of Multi-omics and Artificial Intelligence of Cardiovascular Diseases, University of South China, Hengyang, Hunan, 421001, China; The First Affiliated Hospital, Department of Cardiology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China; Clinical Research Center for Myocardial Injury in Hunan Province, Hengyang, Hunan, 421001, China; The First Affiliated Hospital, Institute of Cardiovascular Disease, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Yali Nie
- Hunan Provincial Key Laboratory of Multi-omics and Artificial Intelligence of Cardiovascular Diseases, University of South China, Hengyang, Hunan, 421001, China; The First Affiliated Hospital, Department of Cardiology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China; Clinical Research Center for Myocardial Injury in Hunan Province, Hengyang, Hunan, 421001, China; The First Affiliated Hospital, Institute of Cardiovascular Disease, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Kai Ding
- The First Affiliated Hospital, Department of Cardiology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Jian Cui
- Hunan Provincial Key Laboratory of Multi-omics and Artificial Intelligence of Cardiovascular Diseases, University of South China, Hengyang, Hunan, 421001, China; Clinical Research Center for Myocardial Injury in Hunan Province, Hengyang, Hunan, 421001, China; The First Affiliated Hospital, Institute of Cardiovascular Disease, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Jinwei Tian
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.
| | - Huifang Tang
- Hunan Provincial Key Laboratory of Multi-omics and Artificial Intelligence of Cardiovascular Diseases, University of South China, Hengyang, Hunan, 421001, China; The First Affiliated Hospital, Department of Cardiology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China; Clinical Research Center for Myocardial Injury in Hunan Province, Hengyang, Hunan, 421001, China; The First Affiliated Hospital, Institute of Cardiovascular Disease, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
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Zare A, Salehpour A, Khoradmehr A, Bakhshalizadeh S, Najafzadeh V, Almasi-Turk S, Mahdipour M, Shirazi R, Tamadon A. Epigenetic Modification Factors and microRNAs Network Associated with Differentiation of Embryonic Stem Cells and Induced Pluripotent Stem Cells toward Cardiomyocytes: A Review. Life (Basel) 2023; 13:life13020569. [PMID: 36836926 PMCID: PMC9965891 DOI: 10.3390/life13020569] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 11/16/2022] [Accepted: 11/16/2022] [Indexed: 02/22/2023] Open
Abstract
More research is being conducted on myocardial cell treatments utilizing stem cell lines that can develop into cardiomyocytes. All of the forms of cardiac illnesses have shown to be quite amenable to treatments using embryonic (ESCs) and induced pluripotent stem cells (iPSCs). In the present study, we reviewed the differentiation of these cell types into cardiomyocytes from an epigenetic standpoint. We also provided a miRNA network that is devoted to the epigenetic commitment of stem cells toward cardiomyocyte cells and related diseases, such as congenital heart defects, comprehensively. Histone acetylation, methylation, DNA alterations, N6-methyladenosine (m6a) RNA methylation, and cardiac mitochondrial mutations are explored as potential tools for precise stem cell differentiation.
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Affiliation(s)
- Afshin Zare
- The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr 7514633196, Iran
| | - Aria Salehpour
- The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr 7514633196, Iran
| | - Arezoo Khoradmehr
- The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr 7514633196, Iran
| | - Shabnam Bakhshalizadeh
- Reproductive Development, Murdoch Children’s Research Institute, Melbourne, VIC 3052, Australia
- Department of Paediatrics, University of Melbourne, Melbourne, VIC 3010, Australia
| | - Vahid Najafzadeh
- Department of Veterinary and Animal Sciences, University of Copenhagen, 1870 Frederiksberg C, Denmark
| | - Sahar Almasi-Turk
- Department of Basic Sciences, School of Medicine, Bushehr University of Medical Sciences, Bushehr 7514633341, Iran
| | - Mahdi Mahdipour
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz 5166653431, Iran
- Department of Reproductive Biology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz 5166653431, Iran
- Correspondence: (M.M.); (R.S.); (A.T.)
| | - Reza Shirazi
- Department of Anatomy, School of Medical Sciences, Medicine & Health, UNSW Sydney, Sydney, NSW 2052, Australia
- Correspondence: (M.M.); (R.S.); (A.T.)
| | - Amin Tamadon
- PerciaVista R&D Co., Shiraz 7135644144, Iran
- Correspondence: (M.M.); (R.S.); (A.T.)
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3
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Hayat R. Dynamics of metabolism and regulation of epigenetics during cardiomyocytes maturation. Cell Biol Int 2022; 47:30-40. [PMID: 36208083 DOI: 10.1002/cbin.11931] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 09/21/2022] [Accepted: 09/24/2022] [Indexed: 11/09/2022]
Abstract
Maturation is the last step of heart growth that prepares the organ over the lifetime of the mammal for powerful, effective, and sustained pumping. Structural, gene expression, physiological, and functional specialties of cardiomyocytes describe this mechanism as the heart transits from fetus to adult phases. The main cornerstones of maturation of cardiomyocytes are reviewed and primary regulatory mechanisms are summarized to facilitate and organize these cellular activities. During embryonic development, cardiomyocytes proliferate rigorously but leave the cell cycle permanently immediately after the parturition of the child and experience terminal differentiation. The activation of a host of genes specific for the mature heart is correlated with the exit from the cell cycle. Even when exposed to mitogenic stimuli, the bulk of mature cardiomyocytes do not re-join the cell cycle. The reason for this permanent exit from the cell cycle is shown to be linked with stable switching off of the genes of the cell cycle directly involved in the G2/M transition phase and cytokinesis development. Researchers also trying to explain the molecular mechanism involved in stable inhibition of the gene and described structural changes (epigenetic and chromatin) in this mechanism. Substantial developments in the future with advances in the scientific platforms used for cardiomyocyte maturation research will broaden our understanding of this mechanism and result in better maturation of cardiomyocyte-derived pluripotent stem cells and effective treatment approaches for cardiovascular diseases.
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Affiliation(s)
- Rabia Hayat
- Institute of Evolution and Marine Biodiversity, Ocean University of China, Qingdao, China
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Kim YJ, Tamadon A, Kim YY, Kang BC, Ku SY. Epigenetic Regulation of Cardiomyocyte Differentiation from Embryonic and Induced Pluripotent Stem Cells. Int J Mol Sci 2021; 22:8599. [PMID: 34445302 PMCID: PMC8395249 DOI: 10.3390/ijms22168599] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 08/05/2021] [Accepted: 08/06/2021] [Indexed: 12/17/2022] Open
Abstract
With the intent to achieve the best modalities for myocardial cell therapy, different cell types are being evaluated as potent sources for differentiation into cardiomyocytes. Embryonic stem cells and induced pluripotent stem cells have great potential for future progress in the treatment of myocardial diseases. We reviewed aspects of epigenetic mechanisms that play a role in the differentiation of these cells into cardiomyocytes. Cardiomyocytes proliferate during fetal life, and after birth, they undergo permanent terminal differentiation. Upregulation of cardiac-specific genes in adults induces hypertrophy due to terminal differentiation. The repression or expression of these genes is controlled by chromatin structural and epigenetic changes. However, few studies have reviewed and analyzed the epigenetic aspects of the differentiation of embryonic stem cells and induced pluripotent stem cells into cardiac lineage cells. In this review, we focus on the current knowledge of epigenetic regulation of cardiomyocyte proliferation and differentiation from embryonic and induced pluripotent stem cells through histone modification and microRNAs, the maintenance of pluripotency, and its alteration during cardiac lineage differentiation.
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Affiliation(s)
- Yong-Jin Kim
- Department of Obstetrics and Gynecology, Korea University College of Medicine, Seoul 08308, Korea;
| | - Amin Tamadon
- Department of Marine Stem Cell and Tissue Engineering, Bushehr University of Medical Sciences, Bushehr 14174, Iran;
| | - Yoon-Young Kim
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul 03080, Korea;
- Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Korea;
- Institute of Reproductive Medicine and Population, Medical Research Center, Seoul National University, Seoul 03080, Korea
| | - Byeong-Cheol Kang
- Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Korea;
| | - Seung-Yup Ku
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul 03080, Korea;
- Institute of Reproductive Medicine and Population, Medical Research Center, Seoul National University, Seoul 03080, Korea
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Zhou W, Ma T, Ding S. Non-viral approaches for somatic cell reprogramming into cardiomyocytes. Semin Cell Dev Biol 2021; 122:28-36. [PMID: 34238675 DOI: 10.1016/j.semcdb.2021.06.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 06/04/2021] [Accepted: 06/23/2021] [Indexed: 11/27/2022]
Abstract
Heart disease is the leading cause of human deaths worldwide. Due to lacking cardiomyocytes with replicative capacity and cardiac progenitor cells with differentiation potential in adult hearts, massive loss of cardiomyocytes after ischemic events produces permanent damage, ultimately leading to heart failure. Cellular reprogramming is a promising strategy to regenerate heart by induction of cardiomyocytes from other cell types, such as cardiac fibroblasts. In contrast to conventional virus-based cardiac reprogramming, non-viral approaches greatly reduce the potential risk that includes disruption of genome integrity by integration of foreign DNAs, expression of exogenous genes with oncogenic potential, and appearance of partially reprogrammed cells harmful for the physiological functions of tissues/organs, which impedes their in-vivo applications. Here, we review the recent progress in development of non-viral approaches to directly reprogram somatic cells towards cardiomyocytes and their therapeutic application for heart regeneration.
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Affiliation(s)
- Wei Zhou
- School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China
| | - Tianhua Ma
- School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China
| | - Sheng Ding
- School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China.
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Rufaihah AJ, Chen CK, Yap CH, Mattar CNZ. Mending a broken heart: In vitro, in vivo and in silico models of congenital heart disease. Dis Model Mech 2021; 14:dmm047522. [PMID: 33787508 PMCID: PMC8033415 DOI: 10.1242/dmm.047522] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Birth defects contribute to ∼0.3% of global infant mortality in the first month of life, and congenital heart disease (CHD) is the most common birth defect among newborns worldwide. Despite the significant impact on human health, most treatments available for this heterogenous group of disorders are palliative at best. For this reason, the complex process of cardiogenesis, governed by multiple interlinked and dose-dependent pathways, is well investigated. Tissue, animal and, more recently, computerized models of the developing heart have facilitated important discoveries that are helping us to understand the genetic, epigenetic and mechanobiological contributors to CHD aetiology. In this Review, we discuss the strengths and limitations of different models of normal and abnormal cardiogenesis, ranging from single-cell systems and 3D cardiac organoids, to small and large animals and organ-level computational models. These investigative tools have revealed a diversity of pathogenic mechanisms that contribute to CHD, including genetic pathways, epigenetic regulators and shear wall stresses, paving the way for new strategies for screening and non-surgical treatment of CHD. As we discuss in this Review, one of the most-valuable advances in recent years has been the creation of highly personalized platforms with which to study individual diseases in clinically relevant settings.
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Affiliation(s)
- Abdul Jalil Rufaihah
- Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228
| | - Ching Kit Chen
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228
| | - Choon Hwai Yap
- Division of Cardiology, Department of Paediatrics, Khoo Teck Puat -National University Children's Medical Institute, National University Health System, Singapore 119228
- Department of Bioengineering, Imperial College London, London, UK
| | - Citra N Z Mattar
- Experimental Fetal Medicine Group, Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228
- Department of Obstetrics and Gynaecology, National University Health System, Singapore 119228
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7
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Kerek EM, Yoon KH, Luo SY, Chen J, Valencia R, Julien O, Waskiewicz AJ, Hubbard BP. A conserved acetylation switch enables pharmacological control of tubby-like protein stability. J Biol Chem 2020; 296:100073. [PMID: 33187986 PMCID: PMC7948452 DOI: 10.1074/jbc.ra120.015839] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 10/30/2020] [Accepted: 11/13/2020] [Indexed: 12/29/2022] Open
Abstract
Tubby-like proteins (TULPs) are characterized by a conserved C-terminal domain that binds phosphoinositides. Collectively, mammalian TULP1-4 proteins play essential roles in intracellular transport, cell differentiation, signaling, and motility. Yet, little is known about how the function of these proteins is regulated in cells. Here, we present the protein–protein interaction network of TULP3, a protein that is responsible for the trafficking of G-protein-coupled receptors to cilia and whose aberrant expression is associated with severe developmental disorders and polycystic kidney disease. We identify several protein interaction nodes linked to TULP3 that include enzymes involved in acetylation and ubiquitination. We show that acetylation of two key lysine residues on TULP3 by p300 increases TULP3 protein abundance and that deacetylation of these sites by HDAC1 decreases protein levels. Furthermore, we show that one of these sites is ubiquitinated in the absence of acetylation and that acetylation inversely correlates with ubiquitination of TULP3. This mechanism is evidently conserved across species and is active in zebrafish during development. Finally, we identify this same regulatory module in TULP1, TULP2, and TULP4 and demonstrate that the stability of these proteins is similarly modulated by an acetylation switch. This study unveils a signaling pathway that links nuclear enzymes to ciliary membrane receptors via TULP3, describes a dynamic mechanism for the regulation of all tubby-like proteins, and explores how to exploit it pharmacologically using drugs.
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Affiliation(s)
- Evan M Kerek
- Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada
| | - Kevin H Yoon
- Department of Biological Sciences, University of Alberta, Edmonton, Alberta, Canada
| | - Shu Y Luo
- Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada
| | - Jerry Chen
- Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada
| | - Robert Valencia
- Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada
| | - Olivier Julien
- Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada
| | - Andrew J Waskiewicz
- Department of Biological Sciences, University of Alberta, Edmonton, Alberta, Canada
| | - Basil P Hubbard
- Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada.
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Alcohol-induced histone H3K9 hyperacetylation and cardiac hypertrophy are reversed by a histone acetylases inhibitor anacardic acid in developing murine hearts. Biochimie 2015; 113:1-9. [DOI: 10.1016/j.biochi.2015.03.012] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2014] [Accepted: 03/11/2015] [Indexed: 01/04/2023]
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Le JM, Squarize CH, Castilho RM. Histone modifications: Targeting head and neck cancer stem cells. World J Stem Cells 2014; 6:511-525. [PMID: 25426249 PMCID: PMC4178252 DOI: 10.4252/wjsc.v6.i5.511] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Revised: 09/10/2014] [Accepted: 09/17/2014] [Indexed: 02/06/2023] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, and is responsible for a quarter of a million deaths annually. The survival rate for HNSCC patients is poor, showing only minor improvement in the last three decades. Despite new surgical techniques and chemotherapy protocols, tumor resistance to chemotherapy remains a significant challenge for HNSCC patients. Numerous mechanisms underlie chemoresistance, including genetic and epigenetic alterations in cancer cells that may be acquired during treatment and activation of mitogenic signaling pathways, such as nuclear factor kappa-light-chain-enhancer-of activated B cell, that cause reduced apoptosis. In addition to dysfunctional molecular signaling, emerging evidence reveals involvement of cancer stem cells (CSCs) in tumor development and in tumor resistance to chemotherapy and radiotherapy. These observations have sparked interest in understanding the mechanisms involved in the control of CSC function and fate. Post-translational modifications of histones dynamically influence gene expression independent of alterations to the DNA sequence. Recent findings from our group have shown that pharmacological induction of post-translational modifications of tumor histones dynamically modulates CSC plasticity. These findings suggest that a better understanding of the biology of CSCs in response to epigenetic switches and pharmacological inhibitors of histone function may directly translate to the development of a mechanism-based strategy to disrupt CSCs. In this review, we present and discuss current knowledge on epigenetic modifications of HNSCC and CSC response to DNA methylation and histone modifications. In addition, we discuss chromatin modifications and their role in tumor resistance to therapy.
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Sharma A, Nguyen H, Geng C, Hinman MN, Luo G, Lou H. Calcium-mediated histone modifications regulate alternative splicing in cardiomyocytes. Proc Natl Acad Sci U S A 2014; 111:E4920-8. [PMID: 25368158 PMCID: PMC4246288 DOI: 10.1073/pnas.1408964111] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
In cardiomyocytes, calcium is known to control gene expression at the level of transcription, whereas its role in regulating alternative splicing has not been explored. Here we report that, in mouse primary or embryonic stem cell-derived cardiomyocytes, increased calcium levels induce robust and reversible skipping of several alternative exons from endogenously expressed genes. Interestingly, we demonstrate a calcium-mediated splicing regulatory mechanism that depends on changes of histone modifications. Specifically, the regulation occurs through changes in calcium-responsive kinase activities that lead to alterations in histone modifications and subsequent changes in the transcriptional elongation rate and exon skipping. We demonstrate that increased intracellular calcium levels lead to histone hyperacetylation along the body of the genes containing calcium-responsive alternative exons by disrupting the histone deacetylase-to-histone acetyltransferase balance in the nucleus. Consequently, the RNA polymerase II elongation rate increases significantly on those genes, resulting in skipping of the alternative exons. These studies reveal a mechanism by which calcium-level changes in cardiomyocytes impact on the output of gene expression through altering alternative pre-mRNA splicing patterns.
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Affiliation(s)
| | | | - Cuiyu Geng
- Department of Genetics and Genome Sciences
| | | | - Guangbin Luo
- Department of Genetics and Genome Sciences, Case Comprehensive Cancer Center, and
| | - Hua Lou
- Department of Genetics and Genome Sciences, Case Comprehensive Cancer Center, and Center for RNA Molecular Biology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106
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11
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Liu HJ, Wang T, Li QM, Guan XY, Xu Q. Knock-down of p300 decreases the proliferation and odontogenic differentiation potentiality of HDPCs. Int Endod J 2014; 48:976-85. [PMID: 25288362 DOI: 10.1111/iej.12392] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2014] [Accepted: 10/02/2014] [Indexed: 01/17/2023]
Abstract
AIM To investigate the role of p300 in the regulation of proliferation and odontogenic differentiation of human dental pulp cells (HDPCs). METHODOLOGY The recombinant lentiviral vector pshRNA-copGFP was used to knock-down p300 expression in HDPCs. Protein level of acetylated H3 was detected. The proliferation of HDPCs was measured using the CCK8 assay. The cell cycle and apoptosis were analysed using flow cytometry and TUNEL staining, respectively. The expression levels of Cdc25A, p21(waf1) and the cleaved products of caspase 3 and caspase 7 were determined utilizing real-time quantitative polymerase chain reaction and Western blotting analysis. The alkaline phosphatase (ALP) activity was measured, and the formation of mineralized nodules was assessed using alizarin red staining after the induction of odontogenic differentiation of HDPCs. The expression levels of the odontogenic differentiation markers DMP-1, DSPP and DSP were detected utilizing real-time quantitative polymerase chain reaction and Western blotting analysis. RESULTS After p300 was knocked down in HDPCs, p300 was significantly down-regulated at both the mRNA and protein levels, and histone H3 acetylation was reduced. The proliferation capacity of HDPCs was suppressed in p300 knock-down groups. The cells were arrested in the G0/G1 phase of the cell cycle, and cell apoptosis was triggered. ALP activity, the formation of mineralized nodules and the expression levels of DMP-1, DSPP and DSP were all decreased in p300-knock-down HDPCs undergoing odontogenic differentiation. CONCLUSION Knocking down p300 restrains the proliferation and odontogenic differentiation potentiality of HDPCs.
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Affiliation(s)
- H J Liu
- Guanghua School of Stomatology & Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - T Wang
- Guanghua School of Stomatology & Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Q M Li
- Guanghua School of Stomatology & Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - X Y Guan
- Guanghua School of Stomatology & Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Q Xu
- Guanghua School of Stomatology & Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, China
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12
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Oyama K, El-Nachef D, Zhang Y, Sdek P, MacLellan WR. Epigenetic regulation of cardiac myocyte differentiation. Front Genet 2014; 5:375. [PMID: 25408700 PMCID: PMC4219506 DOI: 10.3389/fgene.2014.00375] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Accepted: 10/07/2014] [Indexed: 12/04/2022] Open
Abstract
Cardiac myocytes (CMs) proliferate robustly during fetal life but withdraw permanently from the cell cycle soon after birth and undergo terminal differentiation. This cell cycle exit is associated with the upregulation of a host of adult cardiac-specific genes. The vast majority of adult CMs (ACMs) do not reenter cell cycle even if subjected to mitogenic stimuli. The basis for this irreversible cell cycle exit is related to the stable silencing of cell cycle genes specifically involved in the progression of G2/M transition and cytokinesis. Studies have begun to clarify the molecular basis for this stable gene repression and have identified epigenetic and chromatin structural changes in this process. In this review, we summarize the current understanding of epigenetic regulation of CM cell cycle and cardiac-specific gene expression with a focus on histone modifications and the role of retinoblastoma family members.
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Affiliation(s)
- Kyohei Oyama
- Division of Cardiology, Department of Medicine, Center for Cardiovascular Biology and Institute for Stem Cell and Regenerative Medicine, University of Washington Seattle, WA, USA
| | - Danny El-Nachef
- Division of Cardiology, Department of Medicine, Center for Cardiovascular Biology and Institute for Stem Cell and Regenerative Medicine, University of Washington Seattle, WA, USA
| | - Yiqiang Zhang
- Division of Cardiology, Department of Medicine, Center for Cardiovascular Biology and Institute for Stem Cell and Regenerative Medicine, University of Washington Seattle, WA, USA
| | - Patima Sdek
- Division of Cardiology, Department of Medicine, Center for Cardiovascular Biology and Institute for Stem Cell and Regenerative Medicine, University of Washington Seattle, WA, USA
| | - W Robb MacLellan
- Division of Cardiology, Department of Medicine, Center for Cardiovascular Biology and Institute for Stem Cell and Regenerative Medicine, University of Washington Seattle, WA, USA
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Karbassi E, Vondriska TM. How the proteome packages the genome for cardiovascular development. Proteomics 2014; 14:2115-26. [PMID: 25074278 DOI: 10.1002/pmic.201400131] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2014] [Revised: 06/24/2014] [Accepted: 07/28/2014] [Indexed: 11/09/2022]
Abstract
The devastating impact of congenital heart defects has made mechanisms of vertebrate heart and vascular development an active area of study. Because myocyte death is a common feature of acquired cardiovascular diseases and the adult heart does not regenerate, the need exists to understand whether features of the developing heart and vasculature-which are more plastic-can be exploited therapeutically in the disease setting. We know that a core network of transcription factors governs commitment to the cardiovascular lineage, and recent studies using genetic loss-of-function approaches and unbiased genomic studies have revealed the role for various chromatin modulatory events. We reason that chromatin structure itself is a causal feature that influences transcriptome complexity along a developmental continuum, and the purpose of this article is to highlight the areas in which 'omics technologies have the potential to reveal new principles of phenotypic plasticity in development. We review the major mechanisms of chromatin structural regulation, highlighting what is known about their actions to control cardiovascular differentiation. We discuss emergent mechanisms of regulation that have been identified on the basis of genomic and proteomic studies of cardiac nuclei and identify current challenges to an integrated understanding of chromatin structure and cardiovascular phenotype.
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Affiliation(s)
- Elaheh Karbassi
- Departments of Anesthesiology, Medicine and Physiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
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Yilbas AE, Hamilton A, Wang Y, Mach H, Lacroix N, Davis DR, Chen J, Li Q. Activation of GATA4 gene expression at the early stage of cardiac specification. Front Chem 2014; 2:12. [PMID: 24790981 PMCID: PMC3982529 DOI: 10.3389/fchem.2014.00012] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Accepted: 02/26/2014] [Indexed: 01/08/2023] Open
Abstract
Currently, there are no effective treatments to directly repair damaged heart tissue after cardiac injury since existing therapies focus on rescuing or preserving reversibly damaged tissue. Cell-based therapies using cardiomyocytes generated from stem cells present a promising therapeutic approach to directly replace damaged myocardium with new healthy tissue. However, the molecular mechanisms underlying the commitment of stem cells into cardiomyocytes are not fully understood and will be critical to guide this new technology into the clinic. Since GATA4 is a critical regulator of cardiac differentiation, we examined the molecular basis underlying the early activation of GATA4 gene expression during cardiac differentiation of pluripotent stem cells. Our studies demonstrate the direct involvement of histone acetylation and transcriptional coactivator p300 in the regulation of GATA4 gene expression. More importantly, we show that histone acetyltransferase (HAT) activity is important for GATA4 gene expression with the use of curcumin, a HAT inhibitor. In addition, the widely used histone deacetylase inhibitor valproic acid enhances both histone acetylation and cardiac specification.
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Affiliation(s)
- Ayse E Yilbas
- Department of Cellular and Molecular Medicine, University of Ottawa Ottawa, ON, Canada
| | - Alison Hamilton
- Department of Pathology and Laboratory Medicine, University of Ottawa Ottawa, ON, Canada
| | - Yingjian Wang
- Department of Pathology and Laboratory Medicine, University of Ottawa Ottawa, ON, Canada
| | - Hymn Mach
- Department of Pathology and Laboratory Medicine, University of Ottawa Ottawa, ON, Canada
| | - Natascha Lacroix
- Department of Cellular and Molecular Medicine, University of Ottawa Ottawa, ON, Canada
| | - Darryl R Davis
- Department of Cellular and Molecular Medicine, University of Ottawa Ottawa, ON, Canada ; Faculty of Medicine, University of Ottawa Heart Institute, University of Ottawa Ottawa, ON, Canada
| | - Jihong Chen
- Department of Pathology and Laboratory Medicine, University of Ottawa Ottawa, ON, Canada
| | - Qiao Li
- Department of Cellular and Molecular Medicine, University of Ottawa Ottawa, ON, Canada ; Department of Pathology and Laboratory Medicine, University of Ottawa Ottawa, ON, Canada
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Tao H, Shi KH, Yang JJ, Huang C, Zhan HY, Li J. Histone deacetylases in cardiac fibrosis: current perspectives for therapy. Cell Signal 2013; 26:521-7. [PMID: 24321371 DOI: 10.1016/j.cellsig.2013.11.037] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2013] [Revised: 11/30/2013] [Accepted: 11/30/2013] [Indexed: 12/17/2022]
Abstract
Cardiac fibrosis is an important pathological feature of cardiac remodeling in heart diseases. The molecular mechanisms of cardiac fibrosis are unknown. Histone deacetylases (HDACs) are enzymes that balance the acetylation activities of histone acetyltransferases on chromatin remodeling and play essential roles in regulating gene transcription. In recent years, the role of HDACs in cardiac fibrosis initiation and progression, as well as the therapeutic effects of HDAC inhibitors, has been well studied. Moreover, numerous studies indicated that HDAC activity is associated with the development and progression of cardiac fibrosis. In this review, the innovative aspects of HDACs are discussed, with respect to biogenesis, their role in cardiac fibrosis. Furthermore, the potential applications of HDAC inhibitors in the treatment of cardiac fibrosis associated with fibroblast activation and proliferation.
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Affiliation(s)
- Hui Tao
- Department of Cardiothoracic Surgery, The Second Hospital of Anhui Medical University, Hefei 230601, China; Cardiovascular Research Center, Anhui Medical University, Hefei 230601, China
| | - Kai-Hu Shi
- Department of Cardiothoracic Surgery, The Second Hospital of Anhui Medical University, Hefei 230601, China; Cardiovascular Research Center, Anhui Medical University, Hefei 230601, China.
| | - Jing-Jing Yang
- School of Pharmacy, Anhui Medical University, Hefei 230032, China; Department of Pharmacology, The Second Hospital of Anhui Medical University, Hefei 230601, China
| | - Cheng Huang
- School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Hong-Ying Zhan
- Department of Cardiothoracic Surgery, The Second Hospital of Anhui Medical University, Hefei 230601, China; Cardiovascular Research Center, Anhui Medical University, Hefei 230601, China
| | - Jun Li
- School of Pharmacy, Anhui Medical University, Hefei 230032, China.
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Wang F, Marshall CB, Ikura M. Transcriptional/epigenetic regulator CBP/p300 in tumorigenesis: structural and functional versatility in target recognition. Cell Mol Life Sci 2013; 70:3989-4008. [PMID: 23307074 PMCID: PMC11113169 DOI: 10.1007/s00018-012-1254-4] [Citation(s) in RCA: 227] [Impact Index Per Article: 18.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2012] [Revised: 11/08/2012] [Accepted: 12/20/2012] [Indexed: 01/19/2023]
Abstract
In eukaryotic cells, gene transcription is regulated by sequence-specific DNA-binding transcription factors that recognize promoter and enhancer elements near the transcriptional start site. Some coactivators promote transcription by connecting transcription factors to the basal transcriptional machinery. The highly conserved coactivators CREB-binding protein (CBP) and its paralog, E1A-binding protein (p300), each have four separate transactivation domains (TADs) that interact with the TADs of a number of DNA-binding transcription activators as well as general transcription factors (GTFs), thus mediating recruitment of basal transcription machinery to the promoter. Most promoters comprise multiple activator-binding sites, and many activators contain tandem TADs, thus multivalent interactions may stabilize CBP/p300 at the promoter, and intrinsically disordered regions in CBP/p300 and many activators may confer adaptability to these multivalent complexes. CBP/p300 contains a catalytic histone acetyltransferase (HAT) domain, which remodels chromatin to 'relax' its superstructure and enables transcription of proximal genes. The HAT activity of CBP/p300 also acetylates some transcription factors (e.g., p53), hence modulating the function of key transcriptional regulators. Through these numerous interactions, CBP/p300 has been implicated in complex physiological and pathological processes, and, in response to different signals, can drive cells towards proliferation or apoptosis. Dysregulation of the transcriptional and epigenetic functions of CBP/p300 is associated with leukemia and other types of cancer, thus it has been recognized as a potential anti-cancer drug target. In this review, we focus on recent exciting findings in the structural mechanisms of CBP/p300 involving multivalent and dynamic interactions with binding partners, which may pave new avenues for anti-cancer drug development.
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Affiliation(s)
- Feng Wang
- Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9 Canada
- Campbell Family Cancer Research Institute, Ontario Cancer Institute, Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 1L7 Canada
- Present Address: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232 USA
| | - Christopher B. Marshall
- Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9 Canada
- Campbell Family Cancer Research Institute, Ontario Cancer Institute, Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 1L7 Canada
| | - Mitsuhiko Ikura
- Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9 Canada
- Campbell Family Cancer Research Institute, Ontario Cancer Institute, Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 1L7 Canada
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Yu Z, Kong J, Pan B, Sun H, Lv T, Zhu J, Huang G, Tian J. Islet-1 may function as an assistant factor for histone acetylation and regulation of cardiac development-related transcription factor Mef2c expression. PLoS One 2013; 8:e77690. [PMID: 24147056 PMCID: PMC3798409 DOI: 10.1371/journal.pone.0077690] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2013] [Accepted: 09/03/2013] [Indexed: 01/15/2023] Open
Abstract
Objective Islet-1 is an important transcription factor for cardiac development through mediating extensive interactions between DNA and proteins. The present study was to investigate the role of Islet-1 in regulating the expression of cardiac development-related transcription factors and mechanism. Methods and Results The expression of Islet-1 and histone acetylases (HATs) subtype p300 was determined in newborn mouse hearts and mouse embryonic hearts at different development stages using Western blot. The expression of Islet-1 and cardiac development-related transcription factors Mef2c, GATA4 and Tbx5 as well as histone H3 acetylation level were determined in cardiac progenitor cells with and without transfection of Islet-1 interference RNA (RNAi) in lentivirus using PCR and Western blot. Islet-1 peak expression occurred on day E14.5 in mouse embryonic heart, and was present in the promoter regions of Mef2c, GATA4 and Tbx5 that were precipitated with p300 antibody. When Islet-1 was inhibited with specific RNAi in cardiac progenitor cells, the expression of Mef2c and Tbx5, but not GATA4, was significantly suppressed along with selective reduction in histone H3 acetylation in the promoter region of Mef2c, but not GATA4 and Tbx5. The level of Mef2c DNA, not GATA4 and Tbx5, in the complex associated with p300 was significantly decreased in the cells with Islet-1 knockdown. Conclusions These data suggested that Islet-1 might function as an assistant factor that was involved in the regulation of histone acetylation and Mef2c expression via assisting p300 on specifically targeting the promoter of Mef2c.
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Affiliation(s)
- Zhongsu Yu
- Heart Centre, Children's Hospital of Chongqing Medical University, Chongqing, PR China
- Key Laboratory of Developmental Disease in Childhood (Chongqing Medical University), Ministry of Education, Chongqing, PR China
| | - Juanjuan Kong
- Heart Centre, Children's Hospital of Chongqing Medical University, Chongqing, PR China
- Key Laboratory of Developmental Disease in Childhood (Chongqing Medical University), Ministry of Education, Chongqing, PR China
| | - Bo Pan
- Heart Centre, Children's Hospital of Chongqing Medical University, Chongqing, PR China
| | - Huichao Sun
- Heart Centre, Children's Hospital of Chongqing Medical University, Chongqing, PR China
| | - Tiewei Lv
- Heart Centre, Children's Hospital of Chongqing Medical University, Chongqing, PR China
| | - Jing Zhu
- Key Laboratory of Developmental Disease in Childhood (Chongqing Medical University), Ministry of Education, Chongqing, PR China
| | - Guoying Huang
- Pediatric Heart Centre, Children's Hospital of Fudan University, Shanghai, PR China
| | - Jie Tian
- Heart Centre, Children's Hospital of Chongqing Medical University, Chongqing, PR China
- * E-mail:
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p300-Mediated Histone Acetylation is Essential for the Regulation of GATA4 and MEF2C by BMP2 in H9c2 Cells. Cardiovasc Toxicol 2013; 13:316-22. [DOI: 10.1007/s12012-013-9212-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
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Zheng M, Zhu J, Lv T, Liu L, Sun H, Tian J. Bone morphogenetic protein‑2 enhances the expression of cardiac transcription factors by increasing histone H3 acetylation in H9c2 cells. Mol Med Rep 2013; 7:953-8. [PMID: 23314833 DOI: 10.3892/mmr.2013.1266] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2012] [Accepted: 01/03/2013] [Indexed: 11/06/2022] Open
Abstract
Bone morphogenetic protein (BMP)‑2 induces the expression of cardiac transcription factors during early heart development, however, the underlying mechanisms for this are not clear. Our previous studies indicated that histone acetylation is critical in the regulation of cardiac gene expression. In the present study, the hypothesis that BMP2 enhances the expression of cardiac transcription factors by increasing histone H3 acetylation was tested. Cultured H9c2 rat embryonic cardiac myocytes were transfected with adenoviruses expressing human BMP2 (AdBMP2). Real‑time RT‑PCR, western blotting, chromatin immunoprecipitation (ChIP) and colorimetric assays were employed to determine gene expression, histone H3 acetylation levels and histone acetylase (HAT) activities. The mRNA expression levels of BMP2, GATA4, MEF2C and p300, but not of Tbx5 and GCN5, were significantly upregulated following transfection with AdBMP2. Similarly, the histone H3 acetylation levels were enhanced in the whole chromatin and in the promoter regions of GATA4 and MEF2C, but not Tbx5, in the transfected cells. The HAT activities were also enhanced. These results indicate that BMP2 is able to upregulate the expression of the cardiac transcription factors GATA4 and MEF2C, in part by increasing histone H3 acetylation in the promoter regions of these genes.
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Affiliation(s)
- Min Zheng
- Heart Centre, Children's Hospital of Chongqing Medical University, Yu Zhong, Chongqing 400014, PR China
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Expression patterns of histone acetyltransferases p300 and CBP during murine tooth development. In Vitro Cell Dev Biol Anim 2011; 48:61-8. [DOI: 10.1007/s11626-011-9472-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2011] [Accepted: 11/10/2011] [Indexed: 01/24/2023]
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Khan SN, Khan AU. Role of histone acetylation in cell physiology and diseases: An update. Clin Chim Acta 2010; 411:1401-11. [PMID: 20598676 DOI: 10.1016/j.cca.2010.06.020] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2010] [Revised: 06/04/2010] [Accepted: 06/16/2010] [Indexed: 01/06/2023]
Abstract
Although the role of histone acetylation in gene regulation has been the subject of many reviews, their impact on cell physiology and pathological states of proliferation, differentiation and genome stability in eukaryotic cells remain to be elucidated. Therefore, this review will discuss the molecular, physiological and biochemical aspects of histone acetylation and focus on the interplay of histone acetyltransferases (HATs) and histone deacetylases (HDACs) in different disease states. Current treatment strategies are mostly limited to enzyme inhibitors, though potential lies in targeting other imperative chromatin remodeling factors involved in gene regulation.
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Affiliation(s)
- Shahper N Khan
- Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh 202002, India
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