Chromatin Remodeling in Cardiovascular Development and Physiology

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Circulation Research (Impact Factor: 11.02). 02/2011; 108(3):378-96. DOI: 10.1161/CIRCRESAHA.110.224287
Source: PubMed


Chromatin regulation provides an important means for controlling cardiac gene expression under different physiological and pathological conditions. Processes that direct the development of normal embryonic hearts and pathology of stressed adult hearts may share general mechanisms that govern cardiac gene expression by chromatin-regulating factors. These common mechanisms may provide a framework for us to investigate the interactions among diverse chromatin remodelers/modifiers and various transcription factors in the fine regulation of gene expression, essential for all aspects of cardiovascular biology. Aberrant cardiac gene expression, triggered by a variety of pathological insults, can cause heart diseases in both animals and humans. The severity of cardiomyopathy and heart failure correlates strongly with abnormal cardiac gene expression. Therefore, controlling cardiac gene expression presents a promising approach to the treatment of human cardiomyopathy. This review focuses on the roles of ATP-dependent chromatin-remodeling factors and chromatin-modifying enzymes in the control of gene expression during cardiovascular development and disease.

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Available from: Ching-Pin Chang, Oct 17, 2014
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    • "Other studies have also detected higher expression levels of RELN in human adult atria (Kaab et al., 2004), although its exact function in the heart is unknown. Chromatin remodelling and histone modifications are also known to have an important role in heart development (Han et al., 2011; Chang and Bruneau, 2012). Genes encoding histones that influence nucleosome structure and are important in compaction of DNA (HIST1H3I, HIST1H2BM, HIST1H2AI) were mainly downregulated in T2 ventricles and atria, and to our knowledge have not previously been described in cardiac development. "
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    ABSTRACT: Differentiated derivatives of human pluripotent stem cells (hPSCs) are often considered immature because they resemble foetal cells more than adult, with hPSC-derived cardiomyocytes (hPSC-CMs) being no exception. Many functional features of these CMs, such as their cell morphology, electrophysiological characteristics, sarcomere organization and contraction force, are underdeveloped compared to adult cardiomyocytes. However relatively little is known on how their gene expression profiles compare to the human foetal heart, in part because of the paucity of data on the human foetal heart at different stages of development. Here, we collected samples of matched ventricles and atria from human foetuses during the first and second trimester of development. This presented a rare opportunity to perform gene expression analysis on the individual chambers of the heart at various stages of development, allowing us to identify genes not only involved in the formation of the heart, but also specific genes upregulated in each of the four chambers and at different stages of development. The data showed that hPSC-CMs had a gene expression profile similar to first trimester foetal heart but after culture in conditions shown previously to induce maturation, they cluster closer to the second trimester foetal heart samples. In summary, we demonstrate how the gene expression profiles of human foetal heart samples can be used for benchmarking hPSC-CMs and also contribute to determining their equivalent stage of development.
    Development 07/2015; · 6.27 Impact Factor
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    • "ncRNAs shorter than 200 nucleotides are usually identified as small/short ncRNA and include PIWI-interacting RNAs (piRNAs), endogeneous small interfering RNAs (siRNAs) and microRNAs (miRNAs) but also classical ncRNAs, such as ribosomal RNAs (rRNAs), transfer RNAs (tRNAs) and small nucleolar RNAs (snoRNAs); whereas those longer than 200 nucleotides are classified as long ncRNAs (lncRNAs). LncRNAs can be classified as lincRNAs (long intergenic non-coding RNAs) that are transcribed adjacent to protein-coding genes, eRNAs (enhancer RNAs that are transcribed within the enhancer regions), intronic lncRNAs (transcribed within the introns of protein-coding genes) and antisense lncRNAs (transcribed from the opposite genomic strand relative to protein-coding genes) [1, 2]. In the past few years, an increasing number of lncRNAs have been discovered in eukaryotic organisms, ranging from nematodes to humans [3–17]. "
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    ABSTRACT: BACKGROUND: The advent of large-scale gene expression technologies has helped to reveal in eukaryotic cells, the existence of thousands of non-coding transcripts, whose function and significance remain mostly poorly understood. Among these non-coding transcripts, long non-coding RNAs (lncRNAs) are the least well-studied but are emerging as key regulators of diverse cellular processes. In the present study, we performed a survey in bovine Longissimus thoraci of lincRNAs (long intergenic non-coding RNAs not overlapping protein-coding transcripts). To our knowledge, this represents the first such study in bovine muscle. RESULTS: To identify lincRNAs, we used paired-end RNA sequencing (RNA-Seq) to explore the transcriptomes of Longissimus thoraci from nine Limousin bull calves. Approximately 14–45 million paired-end reads were obtained per library. A total of 30,548 different transcripts were identified. Using a computational pipeline, we defined a stringent set of 584 different lincRNAs with 418 lincRNAs found in all nine muscle samples. Bovine lincRNAs share characteristics seen in their mammalian counterparts: relatively short transcript and gene lengths, low exon number and significantly lower expression, compared to protein-encoding genes. As for the first time, our study identified lincRNAs from nine different samples from the same tissue, it is possible to analyse the inter-individual variability of the gene expression level of the identified lincRNAs. Interestingly, there was a significant difference when we compared the expression variation of the 418 lincRNAs with the 10,775 known selected protein-encoding genes found in all muscle samples. In addition, we found 2,083 pairs of lincRNA/proteinencoding genes showing a highly significant correlated expression. Fourteen lincRNAs were selected and 13 were validated by RT-PCR. Some of the lincRNAs expressed in muscle are located within quantitative trait loci for meat quality traits. CONCLUSIONS: Our study provides a glimpse into the lincRNA content of bovine muscle and will facilitate future experimental studies to unravel the function of these molecules. It may prove useful to elucidate their effect on mechanisms underlying the genetic variability of meat quality traits. This catalog will complement the list of lincRNAs already discovered in cattle and therefore will help to better annotate the bovine genome.
    BMC Genomics 06/2014; 15(1):499. DOI:10.1186/1471-2164-15-499 · 3.99 Impact Factor
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    • "Cardiac hypertrophy is associated with a shift in myosin heavy chain (MHC) gene expression (3). Chromatin-modifying enzymes and non-coding RNAs (ncRNAs) are thought to mediate gene regulatory functions in cardiac hypertrophy (4,5). Chromatin remodeling complexes such as Brg1 and HDAC enzymes are known to regulate genes implicated in hypertrophy by directly associating to the intergenic bi-directional promoter (bdP) of the α- and β-MHC genes (6). "
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    ABSTRACT: The Polycomb-group protein, Ezh2, is required for epigenetic gene silencing in the adult heart by unknown mechanism. We investigated the role of Ezh2 and non-coding RNAs in a mouse model of pressure overload using transverse aortic constriction (TAC) attenuated by the prototypical histone deacetylase inhibitor, trichostatin A (TSA). Chromatin immunoprecipitation of TAC and TAC+TSA hearts suggests interaction of Ezh2 and primary microRNA-208b (pri-miR-208b) in the regulation of hypertrophic gene expression. RNAi silencing of pri-miR-208b and Ezh2 validate pri-miR-208b-mediated transcriptional silencing of genes implicated in cardiac hypertrophy including the suppression of the bi-directional promoter (bdP) of the cardiac myosin heavy chain genes. In TAC mouse heart, TSA attenuated Ezh2 binding to bdP and restored antisense β-MHC and α-MHC gene expression. RNA-chromatin immunoprecipitation experiments in TAC hearts also show increased pri-miR-208b dependent-chromatin binding. These results are the first description by which primary miR interactions serve to integrate chromatin modifications and the transcriptional response to distinct signaling cues in the heart. These studies provide a framework for MHC expression and regulation of genes implicated in pathological remodeling of ventricular hypertrophy.
    Nucleic Acids Research 10/2013; DOI:10.1093/nar/gkt896 · 9.11 Impact Factor
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