Download or read book Regulation of Cardiac Gene Expression by Transcriptional an Epigenetic Mechanism and Identification of a Novel Chromatin Remodeling Factor written by Jenny Schlesinger and published by . This book was released on 2011 with total page 186 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Regulation of Cardiac Gene Expression by Transcriptional and Epigenetic Mechanisms and Identification of a Novel Chromatin Remodeling Factor written by and published by . This book was released on 2011 with total page 186 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Epigenetics in Cardiac Disease written by Johannes Backs and published by Springer. This book was released on 2016-11-21 with total page 322 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book describes important advances in our understanding of how environmental conditions affect cardiac gene expression through epigenetic mechanisms. Further, it discusses the roles of chromatin modifications (in particular DNA methylation and histone modifications) and of chromatin regulators in the context of cardiac diseases. The book provides readers with an overview of our current understanding of epigenetic regulation in the heart, and will stimulate further research in this exciting field. Edited and written by internationally respected experts, it addresses the needs of professors, students and researchers working in the fields of cardiac biology and epigenetics.

Download or read book Cardiac Gene Expression written by Jun Zhang and published by Springer Science & Business Media. This book was released on 2008-02-03 with total page 741 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book presents both cutting-edge and established methods for studying cardiac gene expression. The protocols provide a template for solid research, and cover the process through screening, analysis, characterization, and functional confirmation of novel genes or known genes with a new function. The concluding section of the book highlights methods that facilitate overexpression or cardiac-specific targeted gene deletion.

Download or read book Gene Activity Patterns Associated with Pathological Cardiac Hypertrophy are Mediated by Specific Chromatin Modifying Factors written by Lisa Hsiu Chuan Chang and published by . This book was released on 2013 with total page 528 pages. Available in PDF, EPUB and Kindle. Book excerpt: Pathological cardiac hypertrophy is an initial compensatory response of the heart to a range of intrinsic stimuli including arterial hypertension, myocardial infarction and cardiomyopathy whereby prolonged stress often results in congestive heart failure and sudden death. This condition is commonly associated with the reactivation of the foetal gene program. Recent work has uncovered the importance of chromatin remodeling in the control of gene expression in heart disease. We used a transverse aortic constricted (TAC) mouse model to induce hypertrophy. The increased expression of Nppa, Nppb and embryonic Myh7 were inversely correlated with reduced expression of the adult Myh6 and Atp2a2 genes in TAC animals. We examined the regulatory complexes associated with hypertrophy and changes in the transcriptional response using strategies that allowed us to immunopurify soluble chromatin fractions. Chromatin immunopurifications were performed on the left ventricles of SHAM and TAC cardiac tissues. Quantification of the immunopurified chromatin indicated a unique pattern of binding on the promoters of Nppa, Nppb, Myh6 and Myh7 genes. Our findings suggested that the ATP-dependent chromatin remodeling complex, SWI/SNF, could act in a coordinated fashion with histone acetyltransferase (HAT) or histone deacetylase (HDAC) complexes to regulate the expression of these genes in the hypertrophic heart. SWI/SNF complex serves as a co-regulator in the development of pathological cardiac hypertrophy. We observed enrichment of SWI/SNF subunit BRM and p300 HAT during the reactivation of the foetal gene program on the promoters of upregulated Nppa, Nppb and Myh7 genes. We also observed the recruitment of the SWI/SNF subunit BRG1 and HDAC2 on the Myh6 gene which was consistent with its suppressed gene expression in the hypertrophic heart. The data presented indicate that components of SWI/SNF machinery are associated with diverse regulatory mechanism and the suppression and activation of gene expression. Suppression of HDACs is known to blunt pressure-overload cardiac hypertrophy. However, the molecular mechanism behind this blockade remains unclear. We used a broad-spectrum HDAC inhibitor, Trichostatin A (TSA) to investigate hypertrophy prevention in a mouse model of TAC. TSA treatment resulted in the downregulation of Nppa, Nppb and embryonic Myh7 which was intrinsically highly expressed in the hypertrophic heart. The observed changes in gene expression were found to be associated with concurrent release of BRM, H3K9/14 acetylation and recruitment of BRG1, HDAC2 on suppressed Nppa, Nppb and Myh6 gene promoters in the TSA treated TAC animals. This study described the reciprocoal association of SWI/SNF subunits, BRG1 and BRM, with histone modifications correlated with the regulation of cardiac gene transcription in pathological hypertrophy and their regulatory function in response to TSA exposure. To determine changes in the expression of genes mediated by pathological cardiac hypertrophy, we used a global approach using RNA-Seq. In recent years, high-throughput technologies have been developed and rapidly improved to interrogate several aspects of cellular processes. RNA-Seq was used to map global mRNA expression profile, providing a more sensitive approach than microarrays. It allowed the identification of rare transcripts and gene isoforms which the array approach was unable to detect. This was followed by further investigation using bioinformatics resources such as gene enrichment analysis, pathways, and regulatory network analysis. This enabled us to classify the differentially expressed genes and transcript isoforms into functional categories. A major challenge in deciphering the molecular mechanism associated with the development and prevention of cardiac hypertrophy is the identification of regulatory determinants that are thought to regulate gene expression. We have identified that SWI/SNF chromatin remodeling complex, more specifically, BRM was associated with HAT whereas BRG1 was associated with HDAC2 in correlation with gene expression. Further investigation of regulatory determinants mediated gene expression would need to be carried out to provide a useful framework for understanding and distinguishing the regulatory function of SWI/SNF in pathological cardiac hypertrophy. These studies could lead to more precise understanding of heart disease and potential new strategy to personalised therapies to prevent or reverse cardiac hypertrophy and in turn, cardiac failure.

Download or read book Control of Cardiac Gene Expression by Chomatin Architectural Proteins written by Emma Marie Monte and published by . This book was released on 2015 with total page 155 pages. Available in PDF, EPUB and Kindle. Book excerpt: When faced with chronic stress, the heart enters a compensatory hypertrophic stage; without intervention it eventually succumbs to decompensation marked by a dilated left ventricular chamber and decreased ejection fraction. While the morphological cardiac remodeling that occurs during the progression of heart failure is well characterized, the exact molecular cause for this gradual switch to failure is not known. In addition to the numerous alterations in signaling pathways, a conserved switch in the transcriptome, known as the fetal gene program, occurs during hypertrophy as a protective effort to sustain contractility by reverting to fetal isoforms of metabolic, contractile and calcium handling genes. We hypothesize that the reproducible, coordinated reprogramming of gene expression is orchestrated by a change in chromatin structure that enables pathologic gene expression. To determine the proteins involved in repackaging chromatin during cardiac pathology, we performed quantitative proteomic analyses of nuclear proteins in a mouse model of pressure overload hypertrophy and failure. Among the hundreds of proteins we measured on chromatin, my subsequent analyses have focused on two candidates that had the potential to alter gene expression by directly affecting chromatin packing. The first was Nucleolin, a major component of the nucleolus where it mediates ribosomal biogenesis. Using isolated myocytes and the developing zebrafish embryo, we uncovered a role for Nucleolin to regulate cardiac looping, with its effect on hypertrophy context dependent, such that in isolated myoctyes knockdown can promote pathologic gene expression, but loss of Nucleolin during development does not alter myocyte size, instead affecting differentiation along the cardiac lineage. The second protein I functionally validated was High mobility group protein B2 (HMGB2), a non-histone chromatin structural protein that increases 3-fold in our proteomic analyses. We show that HMGB2 is necessary for ribosomal RNA transcription and is enriched in the nucleolus in hypertrophy; however, overexpression of HMGB2 shuts down transcription globally by compacting DNA. Furthermore, we find HMGB2 knockdown alters the chromatin environment of individual gene promoters in the same manner as hypertrophic agonist signaling in isolated myocytes. Finally, we find that the effect of HMGB2 abundance on the expression of individual genes can be partially explained by the chromatin context, and specifically identify a novel relationship between HMGB2 and CTCF. These studies add to the growing body of work characterizing chromatin remodeling in hypertrophy, and demonstrate that this remodeling extends outside of gene bodies and promoters. Finally, this work begins to uncover what features of chromatin are responsible for tailoring the effects of ubiquitous chromatin proteins toward a cell-type specific outcome.

Download or read book Epigenetic Contributions in Autoimmune Disease written by Esteban Ballestar and published by Springer. This book was released on 2011-08-23 with total page 182 pages. Available in PDF, EPUB and Kindle. Book excerpt: This volume focuses on the relevance of epigenetic mechanisms in autoimmune disease. It provides new directions for future research in autoimmune disease.

Download or read book Epigenetic Regulators of Cardiac Hypertrophy and Failure written by Shanxi Jiang and published by . This book was released on 2018 with total page 169 pages. Available in PDF, EPUB and Kindle. Book excerpt: Under pathological stress, an otherwise healthy heart may enter hypertrophy, a partially-reversible, compromised state wherein heart function is relatively normal although the muscle cells increase in size. Should the stress continue, however, the heart will succumb to the irreversible condition of heart failure, resulting in an inability to efficaciously pump enough blood to support bodily demands. When the heart enters states of either hypertrophy or failure, noticeable changes in chromatin accessibility and gene expression arise. Chromatin accessibility can be defined by a binary chromatin state model: heterochromatin is tightly packed and contains silenced genes, while the relatively loose conformation of euchromatin is more conductive to active gene transcription. Alternations in gene expression or epigenetic regulation are revealed using high-throughput sequencing techniques, which have been developed and rigorously applied over the last two decades. How the principles revealed from studies of chromatin impact gene expression levels in the diseased heart is unknown. My dissertation studied the role of multiple chromatin regulator factors, as studied by high-throughput sequencing techniques, contribute to function of the normal and diseased heart. Those factors include a histone modifying enzyme, a nucleosome remodeling protein, circular RNAs and DNA methylation. The first two chapters of my dissertation detail the functions of two chromatin remodelers identified by quantitative proteomics using mouse hypertrophy and heart failure models: Smyd1, a histone methyltransferase coding gene containing the SET and MYND domains, and Napl14, nucleosome assembly protein 1-like 4. Chapter 1 reports that the chromatin-binding protein Smyd1 restricts adult mammalian heart growth. Mice with induced knockdown of cardiac-specific Smyd1 displayed cardiomyocyte growth, organ remodeling, and declined heart function. Chapter 2 describes a possible mechanism by which histone chaperone Nap1l4 may regulate cardiac transcription in hypertrophy. As revealed by siRNA knock down, the lack of Nap1l4-mediated transcription reduces the size of neonatal rat ventricular myocytes (NRVMs) and inhibits fetal gene reprogramming induced by phenylephrine (PHE). However, when Nap1l4 is overexpressed, there is an increase in the size of NRVMs. The latter two chapters of the dissertation describe the epigenomic changes revealed by high-throughput sequencing that could potentially affect gene expression during cardiovascular diseases. Chapter 3 explores our utilization of Ribo-Zero RNA sequencing to discover circular RNAs (circRNAs) in the heart using mouse models. We confirmed the existence of cardiac-related circRNAs including circMyocd, circRyr2, and circTtn. With the successful knockdown of circMyocd in NRVMs, we observed increased expression of linear Myocd, indicating the circRNAs may regulate transcription of its linear counterparts. Chapter 4 characterizes DNA methylation alterations in patients undergoing coronary artery bypass grafting (CABG) using reduced representation bisulfite sequencing (RRBS) with respect to post-operative atrial fibrillation (POAF). When comparing pre-operative and post-operative epigenomic states, we found that the hypervariable CpG sites are mostly enriched in or around genes pertaining to the immune system, cellular adhesion and the cardiovascular system. Specifically, altered CpG methylation in genes coding for transforming growth factor-beta 1 (TGF- 1) may be a marker for POAF as well as pre-operative and post-operative epigenomic states. My dissertation revealed that epigenetic changes including chromatin remodelers, DNA methylation and circRNAs could affect the gene expression during heart diseases. The work will undoubtedly benefit the whole community and shed light on the translational medicine for heart failure patients.

Download or read book Cardiac Regeneration written by Masaki Ieda and published by Springer. This book was released on 2017-10-27 with total page 274 pages. Available in PDF, EPUB and Kindle. Book excerpt: This Volume of the series Cardiac and Vascular Biology offers a comprehensive and exciting, state-of-the-art work on the current options and potentials of cardiac regeneration and repair. Several techniques and approaches have been developed for heart failure repair: direct injection of cells, programming of scar tissue into functional myocardium, and tissue-engineered heart muscle support. The book introduces the rationale for these different approaches in cell-based heart regeneration and discusses the most important considerations for clinical translation. Expert authors discuss when, why, and how heart muscle can be salvaged. The book represents a valuable resource for stem cell researchers, cardiologists, bioengineers, and biomedical scientists studying cardiac function and regeneration.

Download or read book Orchestration of Cardiac Gene Expression Mediated by Global Chromatin Architecture written by Elaheh Karbassi and published by . This book was released on 2016 with total page 240 pages. Available in PDF, EPUB and Kindle. Book excerpt: The underlying mechanisms by which cell identity is achieved in a cell type-specific manner during development are unknown. In this project, we examine the mechanisms through which genomic architecture is regulated by different protein factors and how these proteins in turn regulate gene expression in the cardiomyocyte. We search for cardiac chromatin structural factors that are important for the establishment of genomic architecture during differentiation. We hypothesized that these candidates would also be implicated in pathological gene expression upon the onset of heart failure. Instead, we found that the expression changes of chromatin structural genes across a panel of different mouse strains were not universal, nor did they correlate with cardiac phenotype after pathological stress. Most of our current knowledge of signaling mechanisms in the heart has stemmed from genetic manipulations in a single mouse strain. Here, we examined well-characterized regulators of cardiac phenotype and showed that the relationships between gene expression and cardiac phenotype are lost when expanding across multiple genetic backgrounds. More importantly, these data demonstrate that there is no single signature gene that drives heart disease (nor is there a single gene whose expression is a biomarker of the condition), highlighting the role of genetic variability to differentially sculpt the transcriptome in the development and progression of complex diseases. In addition, our findings demonstrate that regulation of gene expression by genetics occurs in a tissue-dependent manner. We previously identified High Mobility Group B2 as an important chromatin structural protein in the heart and showed its involvement in pathological gene expression. These studies suggested this regulation occurs by remodeling global transcriptional activity. To characterize structural organization of cellular transcription, we show that transcriptional activity is compartmentalized into stable factories in the heart that undergo functional changes in vivo in response to disease stimuli. We provide evidence of direct reorganization of genomic structure by showing that nuclear positioning of cardiac genes with respect to chromatin environments and transcription factories correlates with changes in their expression. In summary, this project explores the mechanisms of cardiac gene regulation and illustrates multiple levels of regulation, with influences from genetics and chromatin architecture.

Download or read book Transcriptional Regulation and Chromatin Remodeling Mechanisms at PHO5 written by Christopher Dumas Carvin and published by . This book was released on 2005 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Regulation of gene expression is vital for proper growth and prevention of disease states. In eukaryotes this regulation occurs in the context of chromatin which creates an inherent barrier for the binding of trans-acting factors, such as transcription factors and RNA polymerase. This dissertation focuses on the role of transcriptional activators and chromatin remodeling coactivators in the regulation of the repressible acid phosphatase gene PHO5. Our studies show that histone methylation at lysine 4 of histone H3 is required for the full repression of PHO5and GAL1-10. We show that bromodomains, a domain conserved in chromatin remodeling coactivators, may function to stabilize binding. Finally, we present a strategy using DNA methyltransferases as in vivo probes to detect DNA-protein interactions and examine chromatin structure. We extend this strategy to zinc-finger proteins which can be engineered to bind to any desired DNA sequence as a means of targeting methylation with potential use in epigenetic silencing.

Download or read book Transcriptional Regulation of Cardiac Hypertrophy and Heart Failure written by and published by . This book was released on 2006 with total page 241 pages. Available in PDF, EPUB and Kindle. Book excerpt: Cardiac hypertrophy and dilatation are mediated by neuro-endocrine factors, internal stretch and stress sensitive signaling pathways, which in turn transduce alterations in cardiac gene expression through specific transcription factors. This dissertation will, in the first section, provide direct evidence for transcription factor myocyte enhancer factor 2 (MEF2) in the regulation of cardiac dilation and fibrosis through reprogramming cardiac gene expression; in the second section, introduce a novel secreted factor growth differentiation factor 15 (GDF15) as a cardiac anti-hypertrophic and protective factor. The MEF2 family of transcription factors have been indirectly implicated as a downstream mediator of hypertrophic signaling pathways. In this dissertation, we demonstrate directly that MEF2 induce dilated cardiomyopathy and the lengthening of myocytes without a primary induction of cardiac hypertrophy. Cardiac-specific overexpression of MEF2A or MEF2C showed spontaneous cardiomyopathy, which was not altered by activated calcineurin, or developed more fulminant disease following pressure overload. In cultured cardiomyocytes, MEF2A and MEF2C overexpression induced sarcomeric disorganization and focal elongation. Mechanistically, MEF2A and MEF2C programmed similar alteration in gene expression that included extracellular matrix remodeling, ion handling, and metabolic genes. Indeed, cultured cardiomyocytes overexpressing MEF2A, or adult myocytes from MEF2A transgenic hearts, showed reduced transient outward currents, suggesting a proximal mechanism underlying MEF2-dependent cardiomyopathy. During the analysis of gene reprogramming by MEF2, we noted dramatic induction of GDF15. GDF15 is induced by conditions that promote hypertrophy and dilation. Transgenic mice with cardiac-specific overexpression of GDF15 were normal, but were partially resistant to induced hypertrophy. GDF15 antagonized induced hypertrophy in cultured cardiomyocyte. Transient expression of GDF15 by intravenous adenoviral delivery, or by direct injection of recombinant protein, attenuated ventricular dilation and heart failure in MLP null mice through an endocrine effect. Conversely, Gdf15 null mice showed enhanced cardiac hypertrophic growth, and a pronounced loss in ventricular performance following stimulation. Mechanistically, GDF15 promoted activation of Smad2/3, which was partially responsible for the anti-hypertrophic effects. These results identify GDF15 as a novel endocrine factor that antagonizes the hypertrophic response and loss of ventricular performance.

Download or read book The Role of Chromatin Modifiers and DNA Methylation in Transcription Regulation During Cardiac Hypertrophy written by Jenny Ying Ying Ooi and published by . This book was released on 2013 with total page 392 pages. Available in PDF, EPUB and Kindle. Book excerpt: At the cellular level, the hypertrophied myocardium is characterized by profound changes in gene transcription. Published literature suggests that histone acetylation/methylation as well as SWI/SNF chromatin remodeling factors may play a role in transcription regulation during cardiac hypertrophy. In addition, histone deacetylase inhibitors (HDACi) are able to attenuate cardiac hypertrophy and the gene program that accompanies the stressed heart. In this thesis, the role of chromatin modification as well as DNA methylation in gene regulation was explored in animal models of cardiac hypertrophy by defining protein-protein and protein-DNA complexes. SWI/SNF protein complexes were examined using coimmunoprecipitation with the SWI/SNF determinant, BRG1, coupled to mass spectrometry (ms). Due to the unexpected limitation of MALDI-ToF-tof ms and the abundance of contractile proteins in the heart, nuclear proteins of interest, including BRG1, could not be detected. An alternative approach was to examine protein-DNA complexes using chromatin immunoprecipitation (ChIP). Histone H3 lysine 9/14 acetylation (H3K9/K14ac) was characterized by massive parallel sequencing (ChIP-Seq), whereas gene expression changes determined by microarray. A mouse model of transverse aortic constriction (TAC) allowed investigation of cardiac hypertrophy, which was attenuated by the HDAC inhibitor, Trichostatin A (TSA). In response to TAC, the majority of genes have reduced H3K9/K14ac content on their promoters. Although TSA induced an increase in global H3K9/K14ac, gene promoters were also hypoacetylated. Differential H3K9/K14ac on a promoter did not necessarily correspond to alterations in gene expression during TAC or TSA prevention. We next focused on gene regulatory epigenetic changes on SERCA2a (a gene target identified from H3K9/K14ac ChIP-Seq). In response to TAC-induced-pathological hypertrophy, reduction in active histone marks as well as enrichment of repressive marks was consistent with suppression of SERCA2a gene expression. In the constitutively active PI3K animals (model of physiological hypertrophy), reduced histone H3 lysine 9 trimethylation (H3K9me3) levels were also associated with SERCA2a gene activation. Taken together, these experimental results suggest that the contribution of H3K9/K14ac to gene expression is not straightforward in the stressed heart. In addition, the data suggests a surprising complexity of gene regulation events that go beyond the traditional view of HDACi mediated histone hyperacetylation in cardiac hypertrophy.

Download or read book Transcriptional Regulation and Epigenetics in Cardiovascular Cells written by Achim Lother and published by . This book was released on 2019 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: The mineralocorticoid receptor (MR), a ligand-activated transcription factor, plays an important role in the pathophysiology of cardiovascular disease. Epigenetic mechanisms such as DNA methylation or histone modifications in addition to the DNA sequence are decisive regulators of cell type-specific transcriptional activity and gene expression by controlling chromatin accessibility. In this review, we summarise the current knowledge about the impact of MR on gene expression in cardiovascular cells. We discuss studies investigating the interaction of MR with epigenetic mechanisms or other transcription factors and their implications for the cardiovascular system. Finally, we compare mechanisms of transcriptional regulation by MR and other nuclear transcription factors. In conclusion, MR is an important regulator of gene expression in cardiovascular cells. Potential mechanisms of cell type-specific transcriptional regulation by MR include interaction with other transcription factors or co-regulators, tethering and post-translational modifications of the MR. Further studies will be needed to clarify the interplay of MR and epigenetic mechanisms.

Download or read book Role of Transcription Factor MITF and SWI SNF Chromatin Remodeling Enzymes Subunit BRG1 in the Regulation of Pathological Cardiac Hypertrophy written by Gaurav Mehta and published by . This book was released on 2015 with total page 76 pages. Available in PDF, EPUB and Kindle. Book excerpt: Cardiovascular disorders are the major cause of death in the western world with a total economic impact in billions of dollars. Heart failure represents a final common end point for various cardiovascular conditions and is responsible for high mortality rates. Cardiac hypertrophy is initiated as a cellular mechanism to protect the heart from increased hemodynamic load and ventricular wall tension. Contrary to physiological hypertrophy, pathological hypertrophy, if prolonged, is associated with increased cardiomyocyte loss and represents the most important factor responsible for heart failure. The hallmark feature of pathological hypertrophy is re-expression of the fetal gene program, which involves interplay between transcription factors and chromatin remodeling enzymes. The Microphthalmia-associated transcription factor (MITF) plays a critical role in the development of pathological cardiac hypertrophy in mice in response to isoproterenol and angiotensin II treatment. However, the transcriptional mechanisms by which MITF promotes cardiac hypertrophy have not been elucidated. Brahma-related gene 1 (BRG1), the catalytic ATPase subunit of the Switching defective/Sucrose Non-Fermenting (SWI/SNF) chromatin remodeling complex regulates cardiac hypertrophy in mice. Nonetheless, the transcriptional circuitry of BRG1 containing SWI/SNF complexes and the interaction with other proteins is not understood. In this study, we tested the hypothesis that MITF promotes pathological cardiac hypertrophy by activating transcription of pro-hypertrophy genes through interactions with the SWI/SNF chromatin remodeling complex. We utilized transverse aorta constriction (TAC) induced pressure overload as an in vivo model of pathological cardiac hypertrophy. The expression of MITF and the BRG1 subunit of the SWI/SNF complex increase coordinately in response to pressure overload. Expression of MITF and BRG1 also increased under in vitro conditions in cardiomyocytes isolated from adult mice when stimulated with angiotensin II. Rat heart-derived H9c2 cardiomyocytes showed a similar response when treated with isoproterenol, a known ß-adrenergic agonist. In H9c2 cells, both MITF and BRG1 were required to increase cardiomyocyte size and activate expression of hypertrophy markers: atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in response to ß-adrenergic stimulation. We detected physical interactions between the heart specific isoform of MITF (MITF-H) and BRG1 in cardiomyocytes as well as HEK 293T cells and found that they cooperate to regulate expression of a pro-hypertrophic transcription factor, GATA4. By utilizing Chromatin immunoprecipitation (ChIP), luciferase, and electrophoretic mobility shift assays, we demonstrate that MITF binds to the E box element in the GATA4 promoter. The binding of MITF facilitates recruitment of BRG1 and is associated with enhanced expression of the GATA4 gene as evidenced by increased Histone3 lysine4 tri-methylation (H3K4me3), an active mark of transcription on the GATA4 promoter. Further, down regulating MITF and BRG1 independently results in a significant abrogation in the expression of the GATA4 gene in H9c2 cells when treated with isoproterenol. Thus, in conclusion, we provide evidence that in hypertrophic cardiomyocytes, MITF is a key transcriptional activator of a pro-hypertrophic gene, GATA4, and this regulation is dependent upon the BRG1 component of the SWI/SNF complex.

Download or read book Long Range Control of Gene Expression written by Veronica van Heyningen and published by Academic Press. This book was released on 2011-09-02 with total page 415 pages. Available in PDF, EPUB and Kindle. Book excerpt: Long-Range Control of Gene Expression covers the current progress in understanding the mechanisms for genomic control of gene expression, which has grown considerably in the last few years as insight into genome organization and chromatin regulation has advanced. Discusses the evolution of cis-regulatory sequences in drosophila Includes information on genomic imprinting and imprinting defects in humans Includes a chapter on epigenetic gene regulation in cancer

Download or read book Regulation of Heart Development Via Transcriptional Enhancers and Epigenetic Modifications written by Scott Adrian Smemo and published by . This book was released on 2012 with total page 104 pages. Available in PDF, EPUB and Kindle. Book excerpt: Determining the genetic underpinnings of normal developmental and abnormal disease processes is central to the field of human genetics. Whereas the completion of the Human Genome Project yielded a genetic parts list, recent work has emphasized understanding how those parts are deployed--how those genes are turned on at the right time and right place. In this thesis, I discuss two major projects designed to explicate the regulation of TBX5, a gene critical to heart development and implicated in severe morphological heart disorders. Birthed from the shortcomings of genome-wide association and exome sequencing studies, the first project assesses the contribution of genetic variation in non-coding, regulatory elements (enhancers) to congenital heart disease (CHD). We first identified 3 enhancers that contribute to TBX5 expression, and subsequently discovered a mutation in one of these elements that destroys its cardiac enhancer activity in mouse. Importantly, we found this variant nucleotide present in the Brazilian population at large. Based on its frequency therein, this variant could contribute to as many cases of CHD as HOS, effectively doubling, as a conservative estimate, the number of cases of CHD attributable to TBX5 variation. The second project also focuses on the regulatory dynamics of heart development, but at the epigenetic level. We hypothesize that the regionalized expression of some genes in the heart is the result of distinct patterns of histone modifications, which potentiate or prohibit their expression. Using ChIP-seq for chromatin marks of activation (H3K4me1) and repression (H3K27me3), in combination with transcriptome profiling via RNA-seq, we found a significant set of genes that demonstrate a coordinated epigenetic program that reinforces regionalized expression. TBX5 fits this pattern, with regionalized cardiac and limb expression correlated with coordinated epigenetic marking. Furthermore, we demonstrate that the trans factors necessary to activate TBX5 are present throughout the heart, implying some other mechanism—which we believe to be epigenetic closure—restricts expression to certain domains. In summary, my work has furthered our understanding of the interactions between cis-regulatory elements and epigenetic marks in determining the spatial, temporal and quantitative expression patterns of genes, as well as illustrated how genetic variation within these cis-regulatory sequences likely underlie the etiology of a significant fraction of human diseases, including congenital malformations.