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剖析调控非编码GWAS位点揭示了纤维细胞因果基因与心力衰竭的病理生理相关性

Richard Gill^1,2,3, Daniel R Lu⁴, Ittai Eres⁴

¹Amgen Global Research, Cambridge, MA, USA.

Nature communications

|October 10, 2025

概括

心脏纤维细胞通过遗传变异影响基因表达,在心力衰竭中发挥作用. 这项研究确定了关键的调节回路,将非编码基因变异与纤维细胞中的心脏病基因连接起来.

科学领域:

基因组学就是基因组学.
心血管生物学心血管生物学
表观遗传学在表观遗传学中,表观遗传学是指表观遗传学.

背景情况:

心力衰竭涉及心脏重塑,包括肌细胞死亡和纤维细胞替代.
心脏纤维细胞可能含有表观遗传因素,将非编码SNP与疾病相关的基因表达联系起来.

研究的目的:

研究心脏纤维细胞中非编码SNP如何影响与心脏病相关的基因表达.
为了确定心脏纤维细胞中受遗传变异干扰的调节元素和基因网络.

主要方法:

从主要的男性心脏纤维细胞生成了高分辨率的Hi-C数据.
整合功能基因组学数据,将远程调节元件与基因促进体联系起来.
利用Perturb-seq在不朽的男性心脏纤维细胞中,以验证调节关系.

主要成果:

在心脏纤维化和心脏病中发挥作用的已确定基因 (GJA1,TBC1D32,CXCL12,IL6R,FURIN).
通过淘汰假定的监管元素,确认了GJA1,CXCL12和FURIN的监管联系.
证明了多原子方法可以绘制与疾病相关的调节电路.

结论:

心脏纤维细胞具有表观遗传背景,非编码SNP会影响疾病相关的基因表达.
多原子分析有效地划分了将遗传变异与心脏病基因连接起来的调节途径.
这些发现突出了纤维细胞表观遗传在心血管疾病发病过程中的作用.

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