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

Zhang, Qing Jun; Chen, Hou-Zao; Wang, Lin; Liu, De-Pei; Hill, Joseph A.; Liu, Zhiping

doi:10.1172/jci46277

Cited by 198 publications

(193 citation statements)

References 40 publications

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“…Interestingly, JMJD1A and JMJD2A expression was also increased 4-and 9-fold, respectively, in neonatal versus adult cardiac myocytes. Accordingly, expression of a known target gene of JMJD2A, FHL1 (30), was also increased 7-fold, while SERCA2a expression was reduced 3-fold. In agreement with elevated JMJD1A and JMJD2A expression, H3K9me2 and H3K9me3 were reduced in the ANP and BNP promoter regions in neonatal versus adult cardiomyocytes ( Figure 6B).…”

Section: Figurementioning

confidence: 98%

“…A recent study revealed that JMJD2A plays an important role in the development of cardiac hypertrophy and failure (30). A major target of JMJD2A demethylase activity was the promoter region of FHL1, a component of the mechanotransducer machinery in the heart that can induce cardiac hypertrophy via a pathway that involves serum response factor (SRF) and myocardin (30). Since ANP is also an SRF/myocardin target gene, JMJD2A augmented ANP expression in response to myocardin in an SRF-sensitive manner (30).…”

Section: Figurementioning

confidence: 99%

“…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). Although in that study, deletion of JMJD2A also reduced the expression of ANP and BNP after pressure overload in vivo, it is unclear whether this was the result of direct epigenetic modifications in the promoter regions of these fetal genes or an indirect consequence of the reduction of cardiac hypertrophy through FHL1-related signaling and/or hemodynamics.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Figurementioning

confidence: 98%

Section: Figurementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

HDAC4 controls histone methylation in response to elevated cardiac load

Hohl

Wagner²,

Reil³

et al. 2013

J. Clin. Invest.

166

138

View full text Add to dashboard Cite

show abstract

“…Neonatal rat ventricular myocytes from 1 to 3-day-old Sprague-Dawley rats were prepared as previously described [37]. Myocytes were cultured under serum-free conditions for 48 h before experiments.…”

Section: Primary Culture Of Neonatal Rat Ventricular Myocytesmentioning

confidence: 99%

Overexpression of a dominant-negative mutant of SIRT1 in mouse heart causes cardiomyocyte apoptosis and early-onset heart failure

Zhang

Tang

et al. 2014

Sci. China Life Sci.

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SIRT1, a mammalian ortholog of yeast silent information regulator 2 (Sir2), is an NAD + -dependent protein deacetylase that plays a critical role in the regulation of vascular function. The current study aims to investigate the functional significance of deacetylase activity of SIRT1 in heart. Here we show that the early postnatal hearts expressed the highest level of SIRT1 deacetylase activity compared to adult and aged hearts. We generated transgenic mice with cardiac-specific expression of a dominant-negative form of the human SIRT1 (SIRT1H363Y), which represses endogenous SIRT1 activity. The transgenic mice displayed dilated atrial and ventricular chambers, and died early in the postnatal period. Pathological, echocardiographic and molecular phenotype confirmed the presence of dilated cardiomyopathy. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling analysis revealed a greater abundance of apoptotic nuclei in the hearts of transgenic mice. Furthermore, we show that cardiomyocyte apoptosis caused by suppression of SIRT1 activity is, at least in part, due to increased p53 acetylation and upregulated Bax expression. These results indicate that dominant negative form of SIRT1 (SIRT1H363Y) overexpression in mouse hearts causes cardiomyocyte apoptosis and early-onset heart failure, suggesting a critical role of SIRT1 in preserving normal cardiac development during the early postnatal period. deacetylase, SIRT1, apoptosis, heart failure Citation:

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“…Jmjd2a promotes the transcriptional activation of the Myog gene and thus contributes to skeletal muscle differentiation [42] . Its expression is upregulated in human hypertrophic cardiomyopathy patients and is found to promote cardiac hypertrophy in pathological conditions [43] . Our data reveal that the expression of Jmjd2a is upregulated in Brychyury + cells, suggesting that Jmjd2a might participate in skeletal muscle and cardiomyocyte differentiation as early as the mesodermal stage.…”

Section: Discussionmentioning

confidence: 99%

Expression profiles of histone lysine demethylases during cardiomyocyte differentiation of mouse embryonic stem cells

et al. 2014

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Aim: Histone lysine demethylases (KDMs) control the lineage commitments of stem cells. However, the KDMs involved in the determination of the cardiomyogenic lineage are not fully defined. The aim of this study was to investigate the expression profiles of KDMs during the cardiac differentiation of mouse embryonic stem cells (mESCs). Methods: An in vitro cardiac differentiation system of mESCs with Brachyury (a mesodermal specific marker) and Flk-1 + /Cxcr4 + (dual cell surface biomarkers) selection was used. The expression profiles of KDMs during differentiation were analyzed using Q-PCR. To understand the contributions of KDMs to cardiomyogenesis, the mESCs on differentiation d 3.5 were sorted by FACS into Brachyury + cells and Brachyury -cells, and mESCs on d 5.5 were sorted into Flk-1 + /Cxcr4 + and Flk-1 -/Cxcr4 -cells. Results: mESCs were differentiated into spontaneously beating cardiomyocytes that were visible in embryoid bodies (EBs) on d 7. On d 12-14, all EBs developed spontaneously beating cardiomyocytes. Among the 16 KDMs examined, the expression levels of Phf8, Jarid1a, Jhdm1d, Utx, and Jmjd3 were increased by nearly 2-6-fold on d 14 compared with those on d 0. Brachyury + cells showed higher expression levels of Jmjd3, Jmjd2a and Jhdm1d than Brachyury -cells. A higher level of Jmjd3 was detected in Flk-1 + /Cxcr4 + cells, whereas the level of Jmjd2c was lower in both Brachyury + cells and Flk-1 + /Cxcr4 + cells. Conclusion: KDMs may play important roles during cardiomyogenesis of mESCs. Our results provide a clue for further exploring the roles of KDMs in the cardiac lineage commitment of mESCs and the potential interference of cardiomyogenesis.

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

Cited by 198 publications

References 40 publications

HDAC4 controls histone methylation in response to elevated cardiac load

HDAC4 controls histone methylation in response to elevated cardiac load

Overexpression of a dominant-negative mutant of SIRT1 in mouse heart causes cardiomyocyte apoptosis and early-onset heart failure

Expression profiles of histone lysine demethylases during cardiomyocyte differentiation of mouse embryonic stem cells

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