Epigenetics in the heart: the role of histone modifications in cardiac remodelling

2013 ◽  
Vol 41 (3) ◽  
pp. 789-796 ◽  
Author(s):  
Asmita Tingare ◽  
Bernard Thienpont ◽  
H. Llewelyn Roderick
Keyword(s):  
Histone Modifications ◽  
Molecular Mechanisms ◽  
Cardiac Development ◽  
Histone H3 ◽  
Cardiomyocyte Proliferation ◽  
Genome Wide ◽  
Pathological Hypertrophy ◽  
Number Of Genes ◽  
Recent Developments

Understanding the molecular mechanisms underlying cardiac development and growth has been a longstanding goal for developing therapies for cardiovascular disorders. The heart adapts to a rise in its required output by an increase in muscle mass and alteration in the expression of a large number of genes. However, persistent stress diminishes the plasticity of the heart, consequently resulting in its maladaptive growth, termed pathological hypertrophy. Recent developments suggest that the concomitant genome-wide remodelling of the gene expression programme is largely driven through epigenetic mechanisms such as post-translational histone modifications and DNA methylation. In the last few years, the distinct functions of histone modifications and of the enzymes catalysing their formation have begun to be elucidated in processes important for cardiac development, disease and cardiomyocyte proliferation. The present review explores how repressive histone modifications, in particular methylation of H3K9 (histone H3 Lys9), govern aspects of cardiac biology.

How do histone modifications contribute to transgenerational epigenetic inheritance in C. elegans?

2020 ◽  
Vol 48 (3) ◽  
pp. 1019-1034 ◽  
Author(s):  
Rachel M. Woodhouse ◽  
Alyson Ashe
Keyword(s):  
Histone Modifications ◽  
Molecular Mechanisms ◽  
Epigenetic Inheritance ◽  
Nematode Caenorhabditis Elegans ◽  
Histone Methyltransferases ◽  
Transgenerational Epigenetic Inheritance ◽  
C Elegans ◽  
Recent Developments ◽  
Gene Regulatory

Gene regulatory information can be inherited between generations in a phenomenon termed transgenerational epigenetic inheritance (TEI). While examples of TEI in many animals accumulate, the nematode Caenorhabditis elegans has proven particularly useful in investigating the underlying molecular mechanisms of this phenomenon. In C. elegans and other animals, the modification of histone proteins has emerged as a potential carrier and effector of transgenerational epigenetic information. In this review, we explore the contribution of histone modifications to TEI in C. elegans. We describe the role of repressive histone marks, histone methyltransferases, and associated chromatin factors in heritable gene silencing, and discuss recent developments and unanswered questions in how these factors integrate with other known TEI mechanisms. We also review the transgenerational effects of the manipulation of histone modifications on germline health and longevity.

Abstract 120: Genome-wide DNA Methylation Analysis Reveals Dynamic Changes in the Cardiac Methylome During Post-natal Heart Development

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Choon Boon Sim ◽  
Mark Ziemann ◽  
K.N. Harikrishnan ◽  
Antony Kaspi ◽  
Jenny Ooi ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Heart Development ◽  
Regulatory Networks ◽  
Muscle Development ◽  
Cardiac Development ◽  
Cardiomyocyte Proliferation ◽  
Dynamic Changes ◽  
Genome Wide ◽  
Cardiac Maturation

Epigenetic modifications have emerged as central players in the coordination of gene expression networks during cardiac development. Much attention has focused on the role of histone modifications during embryonic heart development, but relatively little is known about the epigenetic control mechanisms that guide post-natal heart maturation. Furthermore, few studies have investigated the role of DNA methylation during cardiac development, despite the fundamental importance of this biological process for transcriptional regulation. The purpose of the current study was to determine whether DNA methylation plays an important role in guiding transcription during the neonatal period, which is an important developmental window for cardiac maturation, including cardiomyocyte cell cycle withdrawal and loss of endogenous regenerative capacity. Here, we interrogated genome-wide changes in transcription and CpG methylation during post-natal cardiac maturation in the mouse (P1 vs. P14). CpG sequencing (CpG-seq) identified 2251 differentially methylated regions (DMRs) between P1 and P14. Intersection of DMRs with different genomic features revealed that 1248 DMRs were associated with promoter regions and transcription start sites. Interestingly, increased methylation of genes associated with well-known signalling pathways for muscle development and differentiation, such as the bone morphogenetic protein, fibroblast growth factor, Wnt and Notch signalling pathways, was associated with transcriptional repression of these regulatory networks at P14. To determine the functional significance of these dynamic changes in the cardiac methylome, we inhibited DNA methylation in vivo by administration of the DNA hypomethylating agent 5-azacytidine from P2 to P12. Post-natal inhibition of DNA methylation caused a marked increase in heart size and was associated with increased cardiomyocyte proliferation. This study provides evidence for widespread alterations in DNA methylation during post-natal heart maturation and suggests that DNA methylation may play an important role in the transcriptional silencing of key regulatory networks for muscle development and cardiomyocyte proliferation during neonatal life.

The Role of the Endothelium in Premature Atherosclerosis: Molecular Mechanisms

2020 ◽  
Vol 27 (7) ◽  
pp. 1041-1051 ◽  
Author(s):  
Michael Spartalis ◽  
Eleftherios Spartalis ◽  
Antonios Athanasiou ◽  
Stavroula A. Paschou ◽  
Christos Kontogiannis ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Low Density Lipoprotein ◽  
Critical Role ◽  
Density Lipoprotein ◽  
Number Of Genes ◽  
Causes Of Mortality ◽  
Artery Disease ◽  
Genetic And Environmental Factors ◽  
Made In

Atherosclerotic disease is still one of the leading causes of mortality. Atherosclerosis is a complex progressive and systematic artery disease that involves the intima of the large and middle artery vessels. The inflammation has a key role in the pathophysiological process of the disease and the infiltration of the intima from monocytes, macrophages and T-lymphocytes combined with endothelial dysfunction and accumulated oxidized low-density lipoprotein (LDL) are the main findings of atherogenesis. The development of atherosclerosis involves multiple genetic and environmental factors. Although a large number of genes, genetic polymorphisms, and susceptible loci have been identified in chromosomal regions associated with atherosclerosis, it is the epigenetic process that regulates the chromosomal organization and genetic expression that plays a critical role in the pathogenesis of atherosclerosis. Despite the positive progress made in understanding the pathogenesis of atherosclerosis, the knowledge about the disease remains scarce.

scholarly journals DNA methylation regulates transcriptional homeostasis of algal endosymbiosis in the coral modelAiptasia

2017 ◽  
Author(s):  
Yong Li ◽  
Yi Jin Liew ◽  
Guoxin Cui ◽  
Maha J Cziesielski ◽  
Noura Zahran ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Molecular Mechanisms ◽  
Model System ◽  
Epigenetic Mechanism ◽  
Symbiotic Relationship ◽  
Epigenetic Mechanisms ◽  
Genome Wide ◽  
Spurious Transcription ◽  
Coral Reef Ecosystems

The symbiotic relationship between cnidarians and dinoflagellates is the cornerstone of coral reef ecosystems. Although research is focusing on the molecular mechanisms underlying this symbiosis, the role of epigenetic mechanisms, which have been implicated in transcriptional regulation and acclimation to environmental change, is unknown. To assess the role of DNA methylation in the cnidarian-dinoflagellate symbiosis, we analyzed genome-wide CpG methylation, histone associations, and transcriptomic states of symbiotic and aposymbiotic anemones in the model systemAiptasia. We find methylated genes are marked by histone H3K36me3 and show significant reduction of spurious transcription and transcriptional noise, revealing a role of DNA methylation in the maintenance of transcriptional homeostasis. Changes in DNA methylation and expression show enrichment for symbiosis-related processes such as immunity, apoptosis, phagocytosis recognition and phagosome formation, and unveil intricate interactions between the underlying pathways. Our results demonstrate that DNA methylation provides an epigenetic mechanism of transcriptional homeostasis during symbiosis.

scholarly journals Chromatin Profiling of the Repetitive and Nonrepetitive Genomes of the Human Fungal Pathogen Candida albicans

mBio ◽  
2019 ◽  
Vol 10 (4) ◽  
Author(s):  
Robert Jordan Price ◽  
Esther Weindling ◽  
Judith Berman ◽  
Alessia Buscaino
Keyword(s):  
Gene Expression ◽  
Candida Albicans ◽  
Histone Modifications ◽  
Chromatin Structure ◽  
Fungal Pathogen ◽  
Histone H3 ◽  
Content Type ◽  
Chromatin States ◽  
Genome Wide ◽  
Chromatin Profiling

ABSTRACT Eukaryotic genomes are packaged into chromatin structures that play pivotal roles in regulating all DNA-associated processes. Histone posttranslational modifications modulate chromatin structure and function, leading to rapid regulation of gene expression and genome stability, key steps in environmental adaptation. Candida albicans, a prevalent fungal pathogen in humans, can rapidly adapt and thrive in diverse host niches. The contribution of chromatin to C. albicans biology is largely unexplored. Here, we generated the first comprehensive chromatin profile of histone modifications (histone H3 trimethylated on lysine 4 [H3K4me3], histone H3 acetylated on lysine 9 [H3K9Ac], acetylated lysine 16 on histone H4 [H4K16Ac], and γH2A) across the C. albicans genome and investigated its relationship to gene expression by harnessing genome-wide sequencing approaches. We demonstrated that gene-rich nonrepetitive regions are packaged into canonical euchromatin in association with histone modifications that mirror their transcriptional activity. In contrast, repetitive regions are assembled into distinct chromatin states; subtelomeric regions and the ribosomal DNA (rDNA) locus are assembled into heterochromatin, while major repeat sequences and transposons are packaged in chromatin that bears features of euchromatin and heterochromatin. Genome-wide mapping of γH2A, a marker of genome instability, identified potential recombination-prone genomic loci. Finally, we present the first quantitative chromatin profiling in C. albicans to delineate the role of the chromatin modifiers Sir2 and Set1 in controlling chromatin structure and gene expression. This report presents the first genome-wide chromatin profiling of histone modifications associated with the C. albicans genome. These epigenomic maps provide an invaluable resource to understand the contribution of chromatin to C. albicans biology and identify aspects of C. albicans chromatin organization that differ from that of other yeasts. IMPORTANCE The fungus Candida albicans is an opportunistic pathogen that normally lives on the human body without causing any harm. However, C. albicans is also a dangerous pathogen responsible for millions of infections annually. C. albicans is such a successful pathogen because it can adapt to and thrive in different environments. Chemical modifications of chromatin, the structure that packages DNA into cells, can allow environmental adaptation by regulating gene expression and genome organization. Surprisingly, the contribution of chromatin modification to C. albicans biology is still largely unknown. For the first time, we analyzed C. albicans chromatin modifications on a genome-wide basis. We demonstrate that specific chromatin states are associated with distinct regions of the C. albicans genome and identify the roles of the chromatin modifiers Sir2 and Set1 in shaping C. albicans chromatin and gene expression.

Cardiomyocyte proliferation in cardiac development and regeneration: a guide to methodologies and interpretations

2015 ◽  
Vol 309 (8) ◽  
pp. H1237-H1250 ◽  
Author(s):  
Marina Leone ◽  
Ajit Magadum ◽  
Felix B. Engel
Keyword(s):  
Cardiac Function ◽  
Molecular Mechanisms ◽  
Cardiac Development ◽  
Cardiac Regeneration ◽  
Experimental Medicine ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Naturally Occurring ◽  
Ability To Regenerate ◽  
Zebrafish Heart

The newt and the zebrafish have the ability to regenerate many of their tissues and organs including the heart. Thus, a major goal in experimental medicine is to elucidate the molecular mechanisms underlying the regenerative capacity of these species. A wide variety of experiments have demonstrated that naturally occurring heart regeneration relies on cardiomyocyte proliferation. Thus, major efforts have been invested to induce proliferation of mammalian cardiomyocytes in order to improve cardiac function after injury or to protect the heart from further functional deterioration. In this review, we describe and analyze methods currently used to evaluate cardiomyocyte proliferation. In addition, we summarize the literature on naturally occurring heart regeneration. Our analysis highlights that newt and zebrafish heart regeneration relies on factors that are also utilized in cardiomyocyte proliferation during mammalian fetal development. Most of these factors have, however, failed to induce adult mammalian cardiomyocyte proliferation. Finally, our analysis of mammalian neonatal heart regeneration indicates experiments that could resolve conflicting results in the literature, such as binucleation assays and clonal analysis. Collectively, cardiac regeneration based on cardiomyocyte proliferation is a promising approach for improving adult human cardiac function after injury, but it is important to elucidate the mechanisms arresting mammalian cardiomyocyte proliferation after birth and to utilize better assays to determine formation of new muscle mass.

New functions for old factors: the role of polyamines during the establishment of pregnancy

2019 ◽  
Vol 31 (7) ◽  
pp. 1228
Author(s):  
Jane C. Fenelon ◽  
Bruce D. Murphy
Keyword(s):  
Molecular Mechanisms ◽  
New Technologies ◽  
Alternative Pathway ◽  
Rapid Expansion ◽  
Polyamine Synthesis ◽  
Recent Developments ◽  
And Function ◽  
Implantation Period ◽  
Synthesis Regulation

Implantation is essential for the establishment of a successful pregnancy, and the preimplantation period plays a significant role in ensuring implantation occurs in a timely and coordinated manner. This requires effective maternal–embryonic signalling, established during the preimplantation period, to synchronise development. Although multiple factors have been identified as present during this time, the exact molecular mechanisms involved are unknown. Polyamines are small cationic molecules that are ubiquitously expressed from prokaryotes to eukaryotes. Despite being first identified over 300 years ago, their essential roles in cell proliferation and growth, including cancer, have only been recently recognised, with new technologies and interest resulting in rapid expansion of the polyamine field. This review provides a summary of our current understanding of polyamine synthesis, regulation and function with a focus on recent developments demonstrating the requirements for polyamines during the establishment of pregnancy up to the implantation stage, in particular the role of polyamines in the control of embryonic diapause and the identification of an alternative pathway for their synthesis in sheep pregnancy. This, along with other novel discoveries, provides new insights into the control of the peri-implantation period in mammals and highlights the complexities that exist in regulating this critical period of pregnancy.

scholarly journals Molecular Mechanisms and Genome-Wide Aspects of PPAR Subtype Specific Transactivation

PPAR Research ◽  
2010 ◽  
Vol 2010 ◽  
pp. 1-12 ◽  
Author(s):  
Anne Bugge ◽  
Susanne Mandrup
Keyword(s):  
Energy Homeostasis ◽  
Target Gene ◽  
Molecular Mechanisms ◽  
Fat Metabolism ◽  
Special Focus ◽  
Peroxisome Proliferator ◽  
Subtype Specificity ◽  
Genome Wide ◽  
Peroxisome Proliferator Activated Receptors

The peroxisome proliferator-activated receptors (PPARs) are central regulators of fat metabolism, energy homeostasis, proliferation, and inflammation. The three PPAR subtypes, PPAR, /, and activate overlapping but also very different target gene programs. This review summarizes the insights into PPAR subtype-specific transactivation provided by genome-wide studies and discusses the recent advances in the understanding of the molecular mechanisms underlying PPAR subtype specificity with special focus on the regulatory role of AF-1.

scholarly journals Therapeutic Potential of Targeting the SUMO Pathway in Cancer

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4402
Author(s):  
Antti Kukkula ◽  
Veera K. Ojala ◽  
Lourdes M. Mendez ◽  
Lea Sistonen ◽  
Klaus Elenius ◽  
...  
Keyword(s):  
Tumor Suppressors ◽  
Protein Function ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Dependent Manner ◽  
Post Translational Modification ◽  
Recent Developments ◽  
Sumo Pathway ◽  
Multiple Levels

SUMOylation is a dynamic and reversible post-translational modification, characterized more than 20 years ago, that regulates protein function at multiple levels. Key oncoproteins and tumor suppressors are SUMO substrates. In addition to alterations in SUMO pathway activity due to conditions typically present in cancer, such as hypoxia, the SUMO machinery components are deregulated at the genomic level in cancer. The delicate balance between SUMOylation and deSUMOylation is regulated by SENP enzymes possessing SUMO-deconjugation activity. Dysregulation of SUMO machinery components can disrupt the balance of SUMOylation, contributing to the tumorigenesis and drug resistance of various cancers in a context-dependent manner. Many molecular mechanisms relevant to the pathogenesis of specific cancers involve SUMO, highlighting the potential relevance of SUMO machinery components as therapeutic targets. Recent advances in the development of inhibitors targeting SUMOylation and deSUMOylation permit evaluation of the therapeutic potential of targeting the SUMO pathway in cancer. Finally, the first drug inhibiting SUMO pathway, TAK-981, is currently also being evaluated in clinical trials in cancer patients. Intriguingly, the inhibition of SUMOylation may also have the potential to activate the anti-tumor immune response. Here, we comprehensively and systematically review the recent developments in understanding the role of SUMOylation in cancer and specifically focus on elaborating the scientific rationale of targeting the SUMO pathway in different cancers.

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