Gilsbach Ralf, Schwaderer Martin, Preissl Sebastian, Grüning Björn A, Kranzhöfer David, Schneider Pedro, Nührenberg Thomas G, Mulero-Navarro Sonia, Weichenhan Dieter, Braun Christian, Dreßen Martina, Jacobs Adam R, Lahm Harald, Doenst Torsten, Backofen Rolf, Krane Markus, Gelb Bruce D, Hein Lutz
Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, 79104, Freiburg, Germany.
Bioinformatics Group, Department of Computer Science, University of Freiburg, 79110, Freiburg, Germany.
Nat Commun. 2018 Jan 26;9(1):391. doi: 10.1038/s41467-017-02762-z.
Epigenetic mechanisms and transcription factor networks essential for differentiation of cardiac myocytes have been uncovered. However, reshaping of the epigenome of these terminally differentiated cells during fetal development, postnatal maturation, and in disease remains unknown. Here, we investigate the dynamics of the cardiac myocyte epigenome during development and in chronic heart failure. We find that prenatal development and postnatal maturation are characterized by a cooperation of active CpG methylation and histone marks at cis-regulatory and genic regions to shape the cardiac myocyte transcriptome. In contrast, pathological gene expression in terminal heart failure is accompanied by changes in active histone marks without major alterations in CpG methylation and repressive chromatin marks. Notably, cis-regulatory regions in cardiac myocytes are significantly enriched for cardiovascular disease-associated variants. This study uncovers distinct layers of epigenetic regulation not only during prenatal development and postnatal maturation but also in diseased human cardiac myocytes.
心肌细胞分化所必需的表观遗传机制和转录因子网络已被揭示。然而，在胎儿发育、出生后成熟以及疾病过程中，这些终末分化细胞的表观基因组重塑情况仍不清楚。在此，我们研究了发育过程中和慢性心力衰竭时心肌细胞表观基因组的动态变化。我们发现，产前发育和出生后成熟的特征是在顺式调控区域和基因区域存在活性CpG甲基化和组蛋白标记的协同作用，以塑造心肌细胞转录组。相比之下，终末期心力衰竭时的病理基因表达伴随着活性组蛋白标记的变化，而CpG甲基化和抑制性染色质标记没有重大改变。值得注意的是，心肌细胞中的顺式调控区域显著富集与心血管疾病相关的变异。这项研究不仅揭示了产前发育和出生后成熟过程中，还揭示了患病人类心肌细胞中不同层次的表观遗传调控。
