Genome‐wide histone methylation profile for heart failure

Kaneda, Ruri; Takada, Shuji; Yamashita, Yuichi; Choi, Young Lim; Nonaka-Sarukawa, Mutsuko; Soda, Manabu; Misawa, Yoshio; Isomura, Tadashi; Shimada, Kazuyuki; Mano, Hiroyuki

doi:10.1111/j.1365-2443.2008.01252.x

Cited by 145 publications

(118 citation statements)

References 19 publications

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“…Although extensive work has been performed to identify signature DCM genes through global expression profiling (Barrans et al 2002;Barth et al 2006;Camargo and Azuaje 2008), little effort has been focused on the epigenetic contribution, with the exception of histone acetylation Kook et al 2003;Montgomery et al 2007;Ha et al 2010;Hang et al 2010). With regard to histone methylation, only two studies have investigated changes in methylation patterns in heart failure (Kaneda et al 2009;Movassagh et al 2010). However, whether it directly contributes to the development of DCM is not known.…”

Section: Dystrophin Is a Key Target Mediating Dot1l Function In The Hmentioning

confidence: 99%

DOT1L regulates dystrophin expression and is critical for cardiac function

Nguyen¹,

Xiao²,

Neppl³

et al. 2011

Genes Dev.

138

114

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Histone methylation plays an important role in regulating gene expression. One such methylation occurs at Lys 79 of histone H3 (H3K79) and is catalyzed by the yeast DOT1 (disruptor of telomeric silencing) and its mammalian homolog, DOT1L. Previous studies have demonstrated that germline disruption of Dot1L in mice resulted in embryonic lethality. Here we report that cardiac-specific knockout of Dot1L results in increased mortality rate with chamber dilation, increased cardiomyocyte cell death, systolic dysfunction, and conduction abnormalities. These phenotypes mimic those exhibited in patients with dilated cardiomyopathy (DCM). Mechanistic studies reveal that DOT1L performs its function in cardiomyocytes through regulating Dystrophin (Dmd) transcription and, consequently, stability of the Dystrophin-glycoprotein complex important for cardiomyocyte viability. Importantly, expression of a miniDmd can largely rescue the DCM phenotypes, indicating that Dmd is a major target mediating DOT1L function in cardiomyocytes. Interestingly, analysis of available gene expression data sets indicates that DOT1L is down-regulated in idiopathic DCM patient samples compared with normal controls. Therefore, our study not only establishes a critical role for DOT1L-mediated H3K79 methylation in cardiomyocyte function, but also reveals the mechanism underlying the role of DOT1L in DCM. In addition, our study may open new avenues for the diagnosis and treatment of human heart disease.

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Section: Dystrophin Is a Key Target Mediating Dot1l Function In The Hmentioning

confidence: 99%

DOT1L regulates dystrophin expression and is critical for cardiac function

Nguyen¹,

Xiao²,

Neppl³

et al. 2011

Genes Dev.

138

114

View full text Add to dashboard Cite

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“…In fact, recent reports indicate that histone methylation is dynamically regulated in inflammatory and metabolic disorders (26)(27)(28). Furthermore, differential methylation patterns for H3K4 and H3K9 occur in the vicinity of various gene clusters of failing human hearts (29). Recently, an important role for JMJD2A (also known as KDM4A) in regulating cardiac hypertrophy in response to long-term pressure overload was revealed, governing H3K9 methylation status in the promoter region of the four-and-a-half LIM domains 1 (FHL1) gene (30).…”

Section: Introductionmentioning

confidence: 99%

HDAC4 controls histone methylation in response to elevated cardiac load

Hohl

Wagner²,

Reil³

et al. 2013

J. Clin. Invest.

166

138

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In patients with heart failure, reactivation of a fetal gene program, including atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), is a hallmark for maladaptive remodeling of the LV. The mechanisms that regulate this reactivation are incompletely understood. Histone acetylation and methylation affect the conformation of chromatin, which in turn governs the accessibility of DNA for transcription factors. Using human LV myocardium, we found that, despite nuclear export of histone deacetylase 4 (HDAC4), upregulation of ANP and BNP in failing hearts did not require increased histone acetylation in the promoter regions of these genes. In contrast, di-and trimethylation of lysine 9 of histone 3 (H3K9) and binding of heterochromatin protein 1 (HP1) in the promoter regions of these genes were substantially reduced. In isolated working murine hearts, an acute increase of cardiac preload induced HDAC4 nuclear export, H3K9 demethylation, HP1 dissociation from the promoter region, and activation of the ANP gene. These processes were reversed in hearts with myocytespecific deletion of Hdac4. We conclude that HDAC4 plays a central role for rapid modifications of histone methylation in response to variations in cardiac load and may represent a target for pharmacological interventions to prevent maladaptive remodeling in patients with heart failure.

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“…However, the role of histone demethylases in the reprogramming of cardiac gene expression in hypertrophic and failing hearts remains elusive. A genome-wide histone methylation profile for heart failure showed a differential marking of trimethylation of H3K4 and H3K9 (H3K4me3 and H3K9me3) in cardiomyocytes during development of heart failure in both animal models and human (19), suggesting that the enzymes responsible for methylation and demethylation of H3K4me3 and H3K9me3 may play a role in cardiac hypertrophy and heart failure.…”

Section: Introductionmentioning

confidence: 99%

The histone trimethyllysine demethylase JMJD2A promotes cardiac hypertrophy in response to hypertrophic stimuli in mice

Zhang¹,

Chen²,

Wang³

et al. 2011

J. Clin. Invest.

198

182

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Cardiac hypertrophy and failure are accompanied by a reprogramming of gene expression that involves transcription factors and chromatin remodeling enzymes. Little is known about the roles of histone methylation and demethylation in this process. To understand the role of JMJD2A, a histone trimethyl demethylase, in cardiac hypertrophy, we generated mouse lines with heart-specific Jmjd2a deletion (hKO) and overexpression (Jmjd2a-Tg). Jmjd2a hKO and Jmjd2a-Tg mice had no overt baseline phenotype, but did demonstrate altered responses to cardiac stresses. While inactivation of Jmjd2a resulted in an attenuated hypertrophic response to transverse aortic constriction-induced (TAC-induced) pressure overload, Jmjd2a-Tg mice displayed exacerbated cardiac hypertrophy. We identified four-and-a-half LIM domains 1 (FHL1), a key component of the mechanotransducer machinery in the heart, as a direct target of JMJD2A. JMJD2A bound to the FHL1 promoter in response to TAC, upregulated FHL1 expression, and downregulated H3K9 trimethylation. Upregulation of FHL1 by JMJD2A was mediated through SRF and myocardin and required its demethylase activity. The expression of JMJD2A was upregulated in human hypertrophic cardiomyopathy patients. Our studies reveal that JMJD2A promotes cardiac hypertrophy under pathological conditions and suggest what we believe to be a novel mechanism for JMJD2A in reprogramming of gene expression involved in cardiac hypertrophy.

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Genome‐wide histone methylation profile for heart failure

Cited by 145 publications

References 19 publications

DOT1L regulates dystrophin expression and is critical for cardiac function

DOT1L regulates dystrophin expression and is critical for cardiac function

HDAC4 controls histone methylation in response to elevated cardiac load

The histone trimethyllysine demethylase JMJD2A promotes cardiac hypertrophy in response to hypertrophic stimuli in mice

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