Browsing by Author "Zhao, Mingming"

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    Epigenetic response to environmental stress: Assembly of BRG1–G9a/GLP–DNMT3 repressive chromatin complex on Myh6 promoter in pathologically stressed hearts
    (Elsevier, 2016-03-04) Han, Pei; Li, Wei; Yang, Jin; Shang, Ching; Lin, Chiou-Hong; Cheng, Wei; Hang, Calvin T.; Cheng, Hsiu-Ling; Chen, Chen-Hao; Wong, Johnson; Xiong, Yiqin; Zhao, Mingming; Drakos, Stavros G.; Ghetti, Andrea; Li, Dean Y.; Bernstein, Daniel; Chen, Huei-sheng Vincent; Quertermous, Thomas; Chang, Ching-Pin; Medicine, School of Medicine
    Chromatin structure is determined by nucleosome positioning, histone modifications, and DNA methylation. How chromatin modifications are coordinately altered under pathological conditions remains elusive. Here we describe a stress-activated mechanism of concerted chromatin modification in the heart. In mice, pathological stress activates cardiomyocytes to express Brg1 (nucleosome-remodeling factor), G9a/Glp (histone methyltransferase), and Dnmt3 (DNA methyltransferase). Once activated, Brg1 recruits G9a and then Dnmt3 to sequentially assemble repressive chromatin—marked by H3K9 and CpG methylation—on a key molecular motor gene (Myh6), thereby silencing Myh6 and impairing cardiac contraction. Disruption of Brg1, G9a or Dnmt3 erases repressive chromatin marks and de-represses Myh6, reducing stress-induced cardiac dysfunction. In human hypertrophic hearts, BRG1–G9a/GLP–DNMT3 complex is also activated; its level correlates with H3K9/CpG methylation, Myh6 repression, and cardiomyopathy. Our studies demonstrate a new mechanism of chromatin assembly in stressed hearts and novel therapeutic targets for restoring Myh6 and ventricular function. The stress-induced Brg1–G9a–Dnmt3 interactions and sequence of repressive chromatin assembly on Myh6 illustrates a molecular mechanism by which the heart epigenetically responds to environmental signals. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel.
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    Pathologic gene network rewiring implicates PPP1R3A as a central regulator in pressure overload heart failure
    (Springer Nature, 2019-06-24) Cordero, Pablo; Parikh, Victoria N.; Chin, Elizabeth T.; Erbilgin, Ayca; Gloudemans, Michael J.; Shang, Ching; Huang, Yong; Chang, Alex C.; Smith, Kevin S.; Dewey, Frederick; Zaleta, Kathia; Morley, Michael; Brandimarto, Jeff; Glazer, Nicole; Waggott, Daryl; Pavlovic, Aleksandra; Zhao, Mingming; Moravec, Christine S.; Tang, W. H. Wilson; Skreen, Jamie; Malloy, Christine; Hannenhalli, Sridhar; Li, Hongzhe; Ritter, Scott; Li, Mingyao; Bernstein, Daniel; Connolly, Andrew; Hakonarson, Hakon; Lusis, Aldons J.; Margulies, Kenneth B.; Depaoli-Roach, Anna A.; Montgomery, Stephen B.; Wheeler, Matthew T.; Cappola, Thomas; Ashley, Euan A.; Biochemistry and Molecular Biology, School of Medicine
    Heart failure is a leading cause of mortality, yet our understanding of the genetic interactions underlying this disease remains incomplete. Here, we harvest 1352 healthy and failing human hearts directly from transplant center operating rooms, and obtain genome-wide genotyping and gene expression measurements for a subset of 313. We build failing and non-failing cardiac regulatory gene networks, revealing important regulators and cardiac expression quantitative trait loci (eQTLs). PPP1R3A emerges as a regulator whose network connectivity changes significantly between health and disease. RNA sequencing after PPP1R3A knockdown validates network-based predictions, and highlights metabolic pathway regulation associated with increased cardiomyocyte size and perturbed respiratory metabolism. Mice lacking PPP1R3A are protected against pressure-overload heart failure. We present a global gene interaction map of the human heart failure transition, identify previously unreported cardiac eQTLs, and demonstrate the discovery potential of disease-specific networks through the description of PPP1R3A as a central regulator in heart failure.