增强子
生物
遗传学
基因敲除
基因
皮特x2
单倍率不足
表型
分子生物学
基因表达
同源盒
作者
Yizheng Jiang,Yuting Peng,Qi Tian,Zhe Cheng,Bei Feng,Junping Hu,Xia Lu,Hui Guo,Kun Xia,Liang Zhou,Zhengmao Hu
出处
期刊:JCI insight
[American Society for Clinical Investigation]
日期:2024-04-09
标识
DOI:10.1172/jci.insight.177032
摘要
Recent studies have uncovered that non-coding sequence variants may relate to Axenfeld-Rieger syndrome (ARS), a rare developmental anomaly with genetic heterogeneity. However, how these genomic regions are functionally and structurally associated with ARS is still unclear. In this study, we performed genome-wide linkage analysis and whole-genome sequencing in a Chinese ARS family and identified a heterozygous deletion of about 570 kb (termed LOH-1) in the intergenic sequence between PITX2 and FAM241A. Knockout of LOH-1 homologous sequences caused ARS phenotypes in mice. RNA-seq and RT-qPCR revealed a significant reduction in Pitx2 gene expression in LOH-1–/– mice, while Foxc1 expression remained unchanged. ChIP-seq and bioinformatics analysis identified a potential enhancer region (LOH-E1) within LOH-1. Deletion of LOH-E1 led to a significant downregulation of the PITX2 gene. Mechanistically, we found a sequence (hg38 chr4:111,399,594-111,399,691) which is on LOH-E1 could regulate PITX2 by binding to RAD21, a critical component of the cohesin complex. Knockdown of RAD21 resulted in reduced PITX2 expression. Collectively, our findings indicate that a potential enhancer sequence which is within LOH-1 may regulate PITX2 expression remotely through cohesin-mediated loop domains, leading to ARS when absent. 2
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