研究揭示轉錄因子NKX2-5與心臟病的關聯

研究揭示轉錄因子NKX2-5與心臟病的關聯

作者：

小柯機器人

發布時間：2019/10/2 13:09:30

美國加州大學舊金山分校Kelly A. Frazer和Michael G. Rosenfeld等研究人員合作揭示等位基因特異性NKX2-5結合與人類心電圖特徵之間的多種遺傳關聯。這一研究成果於2019年9月30日在線發表於國際學術期刊《自然—遺傳學》。

研究人員介紹，通過全基因組關聯研究（GWAS），心臟轉錄因子（TF）基因NKX2-5被發現與心電圖（EKG）性狀相關，但是在常見調控變異體上NKX2-5的差異性結合對這些性狀的貢獻程度尚未研究。

研究人員分析了來自七個相關個體的誘導多能幹細胞來源心肌細胞的轉錄組學和表觀基因組數據，並確定了與NKX2-5結合的等位基因特異性作用（ASE-SNV）相關的約2000個單核苷酸變體。NKX2-5 ASE-SNV富含改變的TF模體、心臟特異性表達定量性狀基因座和EKG GWAS信號。通過將精細映射與誘導性多能幹細胞來源心肌細胞的表觀基因組數據相結合，研究人員對EKG性狀的候選因果變異進行了優先排序，其中許多是NKX2-5 ASE-SNV。對兩個NKX2-5 ASE-SNV（rs3807989和rs590041）進行實驗性表徵表明，它們通過心臟細胞中的差異蛋白結合來調節靶基因的表達，從而揭示它們是EKG GWAS信號的基礎功能變體。這些結果表明，在整個基因組的許多調控變異體上，差異性NKX2-5結合有助於EKG表型。

附：英文原文

Title: Allele-specific NKX2-5 binding underlies multiple genetic associations with human electrocardiographic traits

Author: Paola Benaglio, Agnieszka DAntonio-Chronowska, Wubin Ma, Feng Yang, William W. Young Greenwald, Margaret K. R. Donovan, Christopher DeBoever, He Li, Frauke Drees, Sanghamitra Singhal, Hiroko Matsui, Jessica van Setten, Nona Sotoodehnia, Kyle J. Gaulton, Erin N. Smith, Matteo DAntonio, Michael G. Rosenfeld, Kelly A. Frazer

Issue&Volume: 2019-09-30

Abstract: The cardiac transcription factor (TF) gene NKX2-5 has been associated with electrocardiographic (EKG) traits through genome-wide association studies (GWASs), but the extent to which differential binding of NKX2-5 at common regulatory variants contributes to these traits has not yet been studied. We analyzed transcriptomic and epigenomic data from induced pluripotent stem cell-derived cardiomyocytes from seven related individuals, and identified ~2,000 single-nucleotide variants associated with allele-specific effects (ASE-SNVs) on NKX2-5 binding. NKX2-5 ASE-SNVs were enriched for altered TF motifs, for heart-specific expression quantitative trait loci and for EKG GWAS signals. Using fine-mapping combined with epigenomic data from induced pluripotent stem cellderived cardiomyocytes, we prioritized candidate causal variants for EKG traits, many of which were NKX2-5 ASE-SNVs. Experimentally characterizing two NKX2-5 ASE-SNVs (rs3807989 and rs590041) showed that they modulate the expression of target genes via differential protein binding in cardiac cells, indicating that they are functional variants underlying EKG GWAS signals. Our results show that differential NKX2-5 binding at numerous regulatory variants across the genome contributes to EKG phenotypes. 

DOI: 10.1038/s41588-019-0499-3

Source:https://www.nature.com/articles/s41588-019-0499-3