Rosa-Garrido Manuel, Chapski Douglas J, Schmitt Anthony D, Kimball Todd H, Karbassi Elaheh, Monte Emma, Balderas Enrique, Pellegrini Matteo, Shih Tsai-Ting, Soehalim Elizabeth, Liem David, Ping Peipei, Galjart Niels J, Ren Shuxun, Wang Yibin, Ren Bing, Vondriska Thomas M
From Departments of Anesthesiology and Perioperative Medicine (M.R.-G., D.J.C., T.H.K., E.K., E.M., T.-T.S., E.S., S.R., Y.W., T.M.V.), Medicine (D.L., P.P., Y.W., T.M.V.), Physiology (P.P.,Y.W., T.M.V.), Molecular, Cellular and Developmental Biology (M.P.), UCLA, Los Angeles, CA; Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City (E.B.); Ludwig Institute for Cancer Research, Department of Cellular and Molecular Medicine, Institute of Genomic Medicine, and Moores Cancer Center, UCSD, San Diego, CA (A.D.S., B.R.); and Department of Cell Biology and Genetics, Erasmus MC, Rotterdam, The Netherlands (N.J.G.).
Circulation. 2017 Oct 24;136(17):1613-1625. doi: 10.1161/CIRCULATIONAHA.117.029430. Epub 2017 Aug 11.
Cardiovascular disease is associated with epigenomic changes in the heart; however, the endogenous structure of cardiac myocyte chromatin has never been determined.
To investigate the mechanisms of epigenomic function in the heart, genome-wide chromatin conformation capture (Hi-C) and DNA sequencing were performed in adult cardiac myocytes following development of pressure overload-induced hypertrophy. Mice with cardiac-specific deletion of CTCF (a ubiquitous chromatin structural protein) were generated to explore the role of this protein in chromatin structure and cardiac phenotype. Transcriptome analyses by RNA-seq were conducted as a functional readout of the epigenomic structural changes.
Depletion of CTCF was sufficient to induce heart failure in mice, and human patients with heart failure receiving mechanical unloading via left ventricular assist devices show increased CTCF abundance. Chromatin structural analyses revealed interactions within the cardiac myocyte genome at 5-kb resolution, enabling examination of intra- and interchromosomal events, and providing a resource for future cardiac epigenomic investigations. Pressure overload or CTCF depletion selectively altered boundary strength between topologically associating domains and A/B compartmentalization, measurements of genome accessibility. Heart failure involved decreased stability of chromatin interactions around disease-causing genes. In addition, pressure overload or CTCF depletion remodeled long-range interactions of cardiac enhancers, resulting in a significant decrease in local chromatin interactions around these functional elements.
These findings provide a high-resolution chromatin architecture resource for cardiac epigenomic investigations and demonstrate that global structural remodeling of chromatin underpins heart failure. The newly identified principles of endogenous chromatin structure have key implications for epigenetic therapy.
心血管疾病与心脏的表观基因组变化相关；然而，心肌细胞染色质的内源性结构从未被确定。
为了研究心脏表观基因组功能的机制，在压力超负荷诱导的肥大发展后，对成年心肌细胞进行了全基因组染色质构象捕获（Hi-C）和DNA测序。构建了心脏特异性缺失CTCF（一种普遍存在的染色质结构蛋白）的小鼠，以探索该蛋白在染色质结构和心脏表型中的作用。通过RNA-seq进行转录组分析，作为表观基因组结构变化的功能读数。
CTCF的缺失足以在小鼠中诱发心力衰竭，接受左心室辅助装置机械卸载的心力衰竭人类患者显示CTCF丰度增加。染色质结构分析揭示了心肌细胞基因组内5 kb分辨率的相互作用，能够检查染色体内和染色体间的事件，并为未来的心脏表观基因组研究提供资源。压力超负荷或CTCF缺失选择性地改变了拓扑相关结构域和A/B区室化之间的边界强度，这是基因组可及性的测量指标。心力衰竭涉及致病基因周围染色质相互作用稳定性的降低。此外，压力超负荷或CTCF缺失重塑了心脏增强子的长程相互作用，导致这些功能元件周围的局部染色质相互作用显著减少。
这些发现为心脏表观基因组研究提供了高分辨率的染色质结构资源，并证明染色质的整体结构重塑是心力衰竭的基础。新发现的内源性染色质结构原理对表观遗传治疗具有关键意义。
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