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

作　　者：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 

机构地区：[1]Biomedical Pioneering Innovation Center,School of Life Sciences,Peking University,Beijing 100871,China [2]Emergency Center,Zhongnan Hospital of Wuhan University,Wuhan 430071,China [3]Beijing Advanced Innovation Center for Genomics(ICG),Ministry of Education Key Laboratory of Cell Proliferation and Differentiation,Beijing 100871,China [4]State Key Laboratory of Cardiovascular Disease,Fuwai Hospital,National Center for Cardiovascular Disease,Chinese Academy of Medical Science and Peking Union Medical College,Beijing 100037,China [5]Peking-Tsinghua Center for Life Sciences,Academy for Advanced Interdisciplinary Studies,Peking University,Beijing 100871,China [6]Department of Cardiovascular Surgery,Fuwai Hospital,National Center for Cardiovascular Diseases,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100037,China [7]Cardiomyopathy Ward,Fuwai Hospital,National Center for Cardiovascular Diseases,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100037,China [8]National Clinical Research Center for Cardiovascular Diseases,Fuwai Hospital,National Center for Cardiovascular Diseases,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100037,China

出　　处：《Protein & Cell》2024年第11期796-817,共22页蛋白质与细胞（英文版）

基　　金：supported by the National Natural Science Foundation of China(Grant No.82170290);the CAMS Innovation Fund for Medical Sciences(Grant No.2023-I2M-1-001);Project funded by China Postdoctoral Science Foundation(Grant No.2023M732704);the Open Research Fund of the National Center for Protein Sciences at Peking University in Beijing.

摘　　要：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.

关 键 词：hypertrophic cardiomyopathy multi-omics chromatin accessibility DNA methylation fetal gene reprogramming therapy 

分 类 号：R542.2[医药卫生—心血管疾病]