Genetic Variation in Enhancers Modifies Cardiomyopathy Gene Expression and Progression.
Genetic Variation in Enhancers Modifies Cardiomyopathy Gene Expression and Progression.
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DOI：
10.1161/circulationaha.120.050432
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发表时间：
2021-03-30
期刊：
影响因子：
37.8
通讯作者：
McNally EM
中科院分区：
文献类型：
--
作者：
Gacita AM;Fullenkamp DE;Ohiri J;Pottinger T;Puckelwartz MJ;Nobrega MA;McNally EM
遗传性心肌病与一系列由遗传和非遗传因素介导的表型相关。非遗传性心肌病也表现出不同的进展和结果。心肌病基因的表达受启动子和增强子的调控，人类启动子和增强子的遗传变异可能导致这种变异。我们叠加了来自心脏和心肌细胞的表观基因组分析，包括启动子捕获染色质构象信息，以鉴定两种心肌病基因MYH7和LMNA的增强子。增强子的功能在诱导多能干细胞衍生的人心肌细胞中得到了验证。我们还进行了全基因组搜索，以确定定位于改变心脏表达的增强子的基因组变异，并使用生物库数据将其中一种变异与心肌病进展联系起来。研究人员鉴定并验证了LMNA和MYH7的多个增强子，包括一个调节MYH6表达向MYH7表达转换的关键增强子。这种增强子的缺失导致MYH6的剂量依赖性增加和工程心脏组织中更快的收缩速率。我们在整个基因组中搜索增强子序列的基因组变异，重点关注产生或中断转录因子结合位点的核苷酸变化。rs875908破坏TBX5结合基序，并从MYH7转录起始位点定位到一个2KB的增强子区域。通过基因编辑去除含有这种变体的增强子，可以显著降低MYH7在人类心肌细胞中的表达。利用生物库数据，rs875908与心肌病的纵向超声心动图特征相关。增强子调节心肌病基因表达，这些增强子区域的基因组变异与心肌病的进展有关。这种综合方法识别了心肌病的非编码修饰因子，并适用于其他心脏基因。
Inherited cardiomyopathy associates with a range of phenotype, mediated by genetic and non-genetic factors. Non-inherited cardiomyopathy also displays varying progression and outcomes. Expression of cardiomyopathy genes is under the regulatory control of promoters and enhancers, and human genetic variation in promoters and enhancers may contribute to this variability. We superimposed epigenomic profiling from hearts and cardiomyocytes, including promoter-capture chromatin conformation information, to identify enhancers for two cardiomyopathy genes, MYH7 and LMNA. Enhancer function was validated in human cardiomyocytes derived from induced pluripotent stem cells. We also conducted a genome-wide search to ascertain genomic variation in enhancers positioned to alter cardiac expression and correlated one of these variants to cardiomyopathy progression using biobank data. Multiple enhancers were identified and validated for LMNA and MYH7, including a key enhancer that regulates the switch from MYH6 expression to MYH7 expression. Deletion of this enhancer resulted in a dose-dependent increase in MYH6 and faster contractile rate in engineered heart tissues. We searched for genomic variation in enhancer sequences across the genome, with focus on nucleotide changes that create or interrupt transcription factor binding sites. rs875908 disrupts a TBX5 binding motif and maps to an enhancer region 2KB from the transcriptional start site of MYH7. Gene editing to remove the enhancer harboring this variant markedly reduced MYH7 expression in human cardiomyocytes. Using biobank-derived data, rs875908 associated with longitudinal echocardiographic features with cardiomyopathy. Enhancers regulate cardiomyopathy gene expression, and genomic variation within these enhancer regions associates with cardiomyopathic progression over time. This integrated approach identified noncoding modifiers of cardiomyopathy and is applicable to other cardiac genes.