动态DNA甲基化调控心肌细胞的发育、成熟及疾病过程。
Dynamic DNA methylation orchestrates cardiomyocyte development, maturation and disease.
作者信息
Gilsbach Ralf, Preissl Sebastian, Grüning Björn A, Schnick Tilman, Burger Lukas, Benes Vladimir, Würch Andreas, Bönisch Ulrike, Günther Stefan, Backofen Rolf, Fleischmann Bernd K, Schübeler Dirk, Hein Lutz
机构信息
Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, Albertstrasse 25, 79104 Freiburg, Germany.
1] Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, Albertstrasse 25, 79104 Freiburg, Germany [2] Hermann Staudinger Graduate School, University of Freiburg, Albertstrasse 21, 79104 Freiburg, Germany.
出版信息
Nat Commun. 2014 Oct 22;5:5288. doi: 10.1038/ncomms6288.
The heart is a highly specialized organ with essential function for the organism throughout life. The significance of DNA methylation in shaping the phenotype of the heart remains only partially known. Here we generate and analyse DNA methylomes from highly purified cardiomyocytes of neonatal, adult healthy and adult failing hearts. We identify large genomic regions that are differentially methylated during cardiomyocyte development and maturation. Demethylation of cardiomyocyte gene bodies correlates strongly with increased gene expression. Silencing of demethylated genes is characterized by the polycomb mark H3K27me3 or by DNA methylation. De novo methylation by DNA methyltransferases 3A/B causes repression of fetal cardiac genes, including essential components of the cardiac sarcomere. Failing cardiomyocytes partially resemble neonatal methylation patterns. This study establishes DNA methylation as a highly dynamic process during postnatal growth of cardiomyocytes and their adaptation to pathological stress in a process tightly linked to gene regulation and activity.
心脏是一个高度特化的器官，在整个生命过程中对生物体具有至关重要的功能。DNA甲基化在塑造心脏表型方面的重要性仍仅部分为人所知。在这里，我们从新生儿、成年健康心脏和成年衰竭心脏的高度纯化心肌细胞中生成并分析DNA甲基化组。我们鉴定出在心肌细胞发育和成熟过程中差异甲基化的大片基因组区域。心肌细胞基因体的去甲基化与基因表达增加密切相关。去甲基化基因的沉默以多梳蛋白标记H3K27me3或DNA甲基化为特征。DNA甲基转移酶3A/B的从头甲基化导致胎儿心脏基因的抑制，包括心脏肌节的重要组成部分。衰竭的心肌细胞部分类似于新生儿的甲基化模式。这项研究将DNA甲基化确立为心肌细胞出生后生长及其在与基因调控和活性紧密相关的过程中对病理应激适应过程中的一个高度动态的过程。
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