Division of Cardiology, Columbia University Irving Medical Center - New York Presbyterian, New York, New York, USA.
Department of Biomedical Engineering, Columbia University, New York, New York, USA.
JCI Insight. 2023 Feb 22;8(4):e161788. doi: 10.1172/jci.insight.161788.
Heart failure (HF) is characterized by global alterations in myocardial DNA methylation, yet little is known about the epigenetic regulation of the noncoding genome and potential reversibility of DNA methylation with left ventricular assist device (LVAD) therapy. Genome-wide mapping of myocardial DNA methylation in 36 patients with HF at LVAD implantation, 8 patients at LVAD explantation, and 7 nonfailing (NF) donors using a high-density bead array platform identified 2,079 differentially methylated positions (DMPs) in ischemic cardiomyopathy (ICM) and 261 DMPs in nonischemic cardiomyopathy (NICM). LVAD support resulted in normalization of 3.2% of HF-associated DMPs. Methylation-expression correlation analysis yielded several protein-coding genes that are hypomethylated and upregulated (HTRA1, FBXO16, EFCAB13, and AKAP13) or hypermethylated and downregulated (TBX3) in HF. A potentially novel cardiac-specific super-enhancer long noncoding RNA (lncRNA) (LINC00881) is hypermethylated and downregulated in human HF. LINC00881 is an upstream regulator of sarcomere and calcium channel gene expression including MYH6, CACNA1C, and RYR2. LINC00881 knockdown reduces peak calcium amplitude in the beating human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). These data suggest that HF-associated changes in myocardial DNA methylation within coding and noncoding genomes are minimally reversible with mechanical unloading. Epigenetic reprogramming strategies may be necessary to achieve sustained clinical recovery from heart failure.
心力衰竭（HF）的特征是心肌 DNA 甲基化的整体改变，但对于非编码基因组的表观遗传调控以及左心室辅助装置（LVAD）治疗中 DNA 甲基化的潜在逆转知之甚少。使用高密度 bead array 平台对 36 例植入 LVAD 的 HF 患者、8 例 LVAD 取出患者和 7 例非衰竭（NF）供体的心肌 DNA 甲基化进行全基因组图谱绘制，在缺血性心肌病（ICM）中确定了 2079 个差异甲基化位置（DMP）和 261 个非缺血性心肌病（NICM）中的 DMP。LVAD 支持导致 3.2%的 HF 相关 DMP 正常化。甲基化-表达相关性分析产生了几个低甲基化和上调的蛋白编码基因（HTRA1、FBXO16、EFCAB13 和 AKAP13）或高甲基化和下调的基因（TBX3）在 HF 中。一种潜在的新型心脏特异性超级增强子长非编码 RNA（lncRNA）（LINC00881）在人类 HF 中呈高甲基化和下调。LINC00881 是肌节和钙通道基因表达的上游调节剂，包括 MYH6、CACNA1C 和 RYR2。LINC00881 的敲低降低了搏动人心诱导多能干细胞衍生心肌细胞（hiPSC-CMs）中的峰值钙幅度。这些数据表明，机械卸载时，编码和非编码基因组中与 HF 相关的心肌 DNA 甲基化变化最小可逆转。表观遗传重编程策略可能是从心力衰竭中获得持续临床恢复所必需的。
