Integrative analysis of transcriptome, DNA methylome, and chromatin accessibility reveals candidate therapeutic targets in hypertrophic cardiomyopathy.

IF 13.6 1区 生物学 Q1 CELL BIOLOGY Protein & Cell Pub Date : 2024-11-01 DOI:10.1093/procel/pwae032
Junpeng Gao, Mengya Liu, Minjie Lu, Yuxuan Zheng, Yan Wang, Jingwei Yang, Xiaohui Xue, Yun Liu, Fuchou Tang, Shuiyun Wang, Lei Song, Lu Wen, Jizheng Wang
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Abstract

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.

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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,其特点是原发性左心室肥厚,通常是由肌纤维基因突变引起的。HCM 的心脏重塑机制仍未完全明了。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。研究人员利用 HCM 患者的心脏组织,通过核糖体占位和甲基组测序(NOMe-seq)和 RNA-seq 分别评估了 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 心脏通过减少肌纤维和代谢基因的表达以及增加细胞外基质基因的表达,恢复到胎儿时期的基因程序。在 DNA 甲基组中,发现了 HCM 中高甲基化和低甲基化的差异甲基化区域(DMR)。在染色质可及性水平上,HCM 心脏的不同基因组元素发生了变化。包括 SP1 和 EGR1 在内的几种转录因子(TFs)在 HCM 的核糖体缺失区(NDRs)表现出胎儿样的结合基序模式。特别是,在携带肌节突变的 HCM 小鼠模型中抑制 SP1 或 EGR1 能明显缓解突变小鼠的 HCM 表型,并逆转胎儿基因重编程。总之,这项研究不仅提供了高精度的 HCM 心脏组织多组学图谱,还揭示了通过干预 HCM 胎儿基因重编程的治疗策略。
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来源期刊
Protein & Cell
Protein & Cell CELL BIOLOGY-
CiteScore
24.00
自引率
0.90%
发文量
1029
审稿时长
6-12 weeks
期刊介绍: Protein & Cell is a monthly, peer-reviewed, open-access journal focusing on multidisciplinary aspects of biology and biomedicine, with a primary emphasis on protein and cell research. It publishes original research articles, reviews, and commentaries across various fields including biochemistry, biophysics, cell biology, genetics, immunology, microbiology, molecular biology, neuroscience, oncology, protein science, structural biology, and translational medicine. The journal also features content on research policies, funding trends in China, and serves as a platform for academic exchange among life science researchers.
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