The histone trimethyllysine demethylase JMJD2A promotes cardiac hypertrophy in response to hypertrophic stimuli in mice
Qing-Jun Zhang, … , Joseph A. Hill, Zhi-Ping Liu
Qing-Jun Zhang, … , Joseph A. Hill, Zhi-Ping Liu
Published May 9, 2011
Citation Information: J Clin Invest. 2011;121(6):2447-2456. https://doi.org/10.1172/JCI46277.
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The histone trimethyllysine demethylase JMJD2A promotes cardiac hypertrophy in response to hypertrophic stimuli in mice

Abstract

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.

Authors

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

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Figure 1

Generation and assessment of a cardiac-specific Jmjd2a KO mouse model.

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Generation and assessment of a cardiac-specific Jmjd2a KO mouse model. ...
(A) Strategy used to delete Jmjd2a in mouse cardiomyocytes and generate the Jmjd2a hKO model. Schematic protein structure of JMJD2A (14) and maps of the WT Jmjd2a locus, the targeting vector, the floxed allele, and the excised allele are shown. Exons are shown in bars. Exon 3 is flanked by loxP sites. (B) Southern blot of tail DNA from a WT (+/+) and a heterozygous (fl/+) mouse using 5′ probe shown in A after digestion with BclI. (C) PCR genotyping on genomic DNA isolated from a WT (+/+), a heterozygous (fl/+), and a homozygous floxed (fl/fl) mouse using primers p1/p2 indicated in A. (D) Western blot demonstrating significantly reduced JMJD2A protein in the heart homogenate of Jmjd2a hKO mice at 4 weeks. (E) H&E stains of representative paraffin sections of control and hKO hearts 3 weeks after sham and TAC operation. (F) HW/BW ratios of control and hKO mice 3 weeks after sham and TAC operation (n = 10–14 per group). The HW/BW ratio after TAC operation was increased 79% compared with sham operation in control mice, whereas it was only increased 42% in hKO mice. (G) Myocyte cross-sectional areas from control and hKO mice (>200 myocytes per heart in randomly selected filed) were assessed (n = 6–8 per group). (H) mRNA transcripts of ANP, BNP, and myh7 in control and hKO mouse hearts after 3 weeks sham and TAC operation. RNAs were normalized to internal GAPDH expression and presented as the fold change relative to control sham samples (n = 4–6 per group). Values are mean ± SEM. *P < 0.05.