Scientists find JMJD2A is upregulated in human hypertrophic cardiomyopathy patients, and protein overexpression in mice exacerbates hypertrophic response to cardiac stress.
Scientists have implicated the histone trimethyl demethylase protein JMJD2A in the development of cardiac hypertrophy. Using mouse models in which the JMJD2A gene was either knocked out or conditionally overexpressed specifically in the heart, the University of Texas Southwestern Medical Center (UTSMC)-led team found that inactivation of the gene lessened the hypertrophic response of the heart to transverse aortic constriction-induced (TAC-induced) pressure overload, whereas animals overexpressing the gene displayed exacerbated cardiac hypertrophy. They also found that expression of JMJD2A was upregulated in human hypertrophic cardiomyopathy patients. The work is published in the Journal of Clinical Investigation in a paper titled “The histone trimethyllysine demethylase JMJD2A promotes cardiac hypertrophy in response to hypertrophic stimuli in mice.”
Histone modifications play important roles in gene transcription, and there has been much investigation into the role of histone acetylation in cardiac remodeling, report Qing-Jun Zhang, Ph.D., and colleagues at UTSMC and the Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing. In contrast, they point out, little is known about the function of histone methylation, even though it is the most abundant form of histone modifications.
JMJD2A/KDM4A is a lysine trimethyl-specific histone demethylase that catalyzes the demethylation of trimethylated H3K9 (H3K9me3) and H3K36 (H3K36me3). A prior genome-wide histone methylation profile for heart failure has already shown 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, the researchers note. This suggests that the enzymes responsible for methylation and demethylation of H3K4me3 and H3K9me3 may also play a role in cardiac hypertrophy and heart failure.
Studies by Dr. Zhang’s team in the JMJD2A-overexpressing and -knockout mice demonstrated that deletion of the gene in the heart attenuated the degree of hypertrophy experienced in response to TAC, whereas overexpression of JMJD2A exacerbated the hypertrophic response. This increase in hypertrophic response was further indicated by significantly larger increases of the expression of cardiac fetal gene markers. Pathological hypertrophy and heart failure are already known to be accompanied by a reprogramming of cardiac gene expression and activation of fetal genes that correlate with loss of cardiac functions, they point out.
Gene profiling of the animals further 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. In response to TAC, JMJD2A bound to the FHL1 promoter upregulated FHL1 expression and downregulated H3K9 trimethylation. Upregulation of FHL1 by JMJD2A was found to be mediated through SRF and myocardin.
Dr. Zhang and colleagues suggest JMJD2A could represent a potential target for the treatment of cardiac hypertrophy. “It will be worth determining in the future whether small molecules designed to target the demethylase activity of JMJD2A could reduce and normalize the expression of SRF/myocardin-targeted genes that are upregulated during cardiac remodeling without compromising the physiological cardiac growth and functions of these genes that are part of the adaptive response to altered conditions.”