Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease and is characterized by primary left ventricular hypertrophy usually caused by mutations in sarcomere genes. The mechanism underlying cardiac remodeling in HCM remains incompletely understood. An investigation of HCM through integrative analysis at multi-omics levels will be helpful for treating HCM. DNA methylation and chromatin accessibility, as well as gene expression, were assessed by nucleosome occupancy and methylome sequencing (NOMe-seq) and RNA-seq, respectively, using the cardiac tissues of HCM patients. Compared with those of the controls, the transcriptome, DNA methylome, and chromatin accessibility of the HCM myocardium showed multifaceted differences. At the transcriptome level, HCM hearts returned to the fetal gene program through decreased sarcomeric and metabolic gene expression and increased extracellular matrix gene expression. In the DNA methylome, hypermethylated and hypomethylated differentially methylated regions were identified in HCM. At the chromatin accessibility level, HCM hearts showed changes in different genome elements. Several transcription factors, including SP1 and EGR1, exhibited a fetal-like pattern of binding motifs in nucleosome-depleted regions in HCM. In particular, the inhibition of SP1 or EGR1 in an HCM mouse model harboring sarcomere mutations markedly alleviated the HCM phenotype of the mutant mice and reversed fetal gene reprogramming. Overall, this study not only provides a high-precision multi-omics map of HCM heart tissue but also sheds light on the therapeutic strategy by intervening in the fetal gene reprogramming in HCM.

中文翻译：

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转录组、DNA 甲基化组和染色质可及性的综合分析揭示了肥厚型心肌病的候选治疗靶点。


肥厚型心肌病 （HCM） 是最常见的遗传性心脏病，其特征是原发性左心室肥厚，通常由肌节基因突变引起。HCM 中心脏重塑的潜在机制仍不完全清楚。通过多组学水平的综合分析对 HCM 进行研究将有助于治疗 HCM。使用 HCM 患者的心脏组织，分别通过核小体占有率和甲基化组测序 （NOMe-seq） 和 RNA-seq 评估 DNA 甲基化和染色质可及性以及基因表达。与对照组相比，HCM 心肌的转录组、 DNA 甲基化组和染色质可及性表现出多方面的差异。在转录组水平上，HCM 心脏通过减少肌节和代谢基因表达以及增加细胞外基质基因表达返回胎儿基因程序。在 DNA 甲基化组中，在 HCM 中鉴定出高甲基化和低甲基化差异甲基化区域。在染色质可及性水平上，HCM 心脏显示出不同基因组元件的变化。几种转录因子，包括 SP1 和 EGR1，在 HCM 的核小体耗尽区域表现出类似胎儿的结合基序模式。特别是，在携带肌节突变的 HCM 小鼠模型中抑制 SP1 或 EGR1 显着减轻了突变小鼠的 HCM 表型并逆转了胎儿基因重编程。总体而言，本研究不仅提供了 HCM 心脏组织的高精度多组学图谱，还通过干预 HCM 中的胎儿基因重编程来阐明治疗策略。