Research

Project 2: Epigenetic regulation of cardiac hypertrophy and heart failure

Epigenetic control via chromatin modification is recognized as a fundamental mechanism for regulating gene expression throughout development and in diseases. However, the role of histone methylation in cardiac biology remains largely unexplored. The fetal gene program is silenced in adult hearts and reactivated during pathological hypertrophic remodeling. Trimethylation of histone 3 lysine 9 (H3K9me3) is a conserved histone modification normally associated with transcriptionally silent chromatins. Removal of H3K9me3 may de-repress transcription. 

To understand the role of H3K9me3 and its specific demethylase JMJD2A in cardiac gene expression during hypertrophic remodeling, 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 an altered response to cardiac stress. While inactivation of JMJD2A resulted in an attenuated hypertrophy in response to transverse aortic constriction (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 at the FHL1 promoter. 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 a novel mechanism for JMJD2A in reprogramming of gene expression involved in cardiac hypertrophy (Zhang et al., JCI 2011).

Currently, we are testing the effect of small molecule inhibitors of JMJD2 family of KDMs in hypertrophic response in cell culture and in animal models of cardiac hypertrophy. We also continue studying how JMJD2A is activated by pathological stimuli and the role of other histone modifications in cardiac hypertrophy and heart failure.