生物
表观遗传学
全基因组关联研究
遗传学
增强子
组蛋白
数量性状位点
单核苷酸多态性
表达数量性状基因座
染色质
表观遗传学
表型
基因
等位基因
基因座(遗传学)
计算生物学
基因表达
DNA甲基化
基因型
作者
Chukwuemeka George Anene Nzelu,Wilson Lek Wen Tan,Eleanor Wong,Mick C J Lee,Matias I. Autio,Susan Mooi Koon Tan,Bangfen P,Michael Morley,Kenneth B. Margulies,Thomas P. Cappola,Marie Loh,John C. Chambers,Shyam Prabhakar,Roger Foo
标识
DOI:10.1161/res.125.suppl_1.368
摘要
Identifying genetic markers for heterogeneous complex diseases such as heart failure has been challenging, and may require prohibitively large cohort sizes in genome-wide association studies (GWAS) in order to meet genome-wide statistical significance. On the other hand, chromatin quantitative trait loci (QTL), elucidated by direct epigenetic profiling of specific human tissues, may contribute towards prioritising sub-threshold variants for disease-association. Here, we captured non-coding genetic variants by performing enhancer H3K27ac ChIP-seq in 70 human control and end-stage failing hearts, mapping out a comprehensive catalogue of 47,321 putative human heart enhancers. 3,897 differential acetylation peaks (FDR 5%) pointed to pathways altered in heart failure (HF). To identify cardiac histone acetylation QTLs (haQTLs), we regressed out confounding factors including HF disease status, and employed the G-SCI test to call out 1,680 haQTLs (FDR 10%). RNA-seq performed on the same heart samples proved a subset of haQTLs to have significant association also to gene expression (expression QTLs), either in cis (180), or through long range interactions (81), identified by Hi-C and Hi-ChIP performed on a subset of hearts. We validated 2 of the haQTLs through base editing to show that the presence of those SNPs indeed affects gene expression in human embryonic stem cells-derived cardiomyocytes. Furthermore, a concordant relationship between the gain or disruption of transcription factor (TF) binding motifs, inferred from alternative alleles at the haQTLs, implied a surprising direct association between these specific TF and local histone acetylation in human hearts. Finally, 62 unique loci were identified by colocalisation of haQTLs with heart-related GWAS datasets. Disease-association for these new loci may indeed be mediated through modification of H3K27-acetylation enrichment and their corresponding gene expression differences.
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