Han, PeiLi, WeiYang, JinShang, ChingLin, Chiou-HongCheng, WeiHang, Calvin T.Cheng, Hsiu-LingChen, Chen-HaoWong, JohnsonXiong, YiqinZhao, MingmingDrakos, Stavros G.Ghetti, AndreaLi, Dean Y.Bernstein, DanielChen, Huei-sheng VincentQuertermous, ThomasChang, Ching-Pin2021-04-232021-04-232016-03-04Han, P., Li, W., Yang, J., Shang, C., Lin, C.-H., Cheng, W., Hang, C. T., Cheng, H.-L., Chen, C.-H., Wong, J., Xiong, Y., Zhao, M., Drakos, S. G., Ghetti, A., Li, D. Y., Bernstein, D., Chen, H. V., Quertermous, T., & Chang, C.-P. (2016). Epigenetic response to environmental stress: Assembly of BRG1–G9a/GLP–DNMT3 repressive chromatin complex on Myh6 promoter in pathologically stressed hearts. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1863(7, Part B), 1772–1781. https://doi.org/10.1016/j.bbamcr.2016.03.0020167-4889https://hdl.handle.net/1805/25727Chromatin 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.en-USHistone methylationDNA methylationChromatin remodelingGene silencingMyosin heavy chainG9aDnmtBrg1H3K9me2Cardiac hypertrophyCardiomyopathyHeart failureArticle