基因座(遗传学)
生物
染色质
遗传学
基因
清脆的
染色体构象捕获
转录因子
增强子
作者
Xubo Huang,Jinxia Huang,Xiumei Li,Jingxian Fan,Desheng Zhou,Hui‐Qi Qu,Joseph Glessner,Dandan Ji,Qi Jia,Zhiyong Ding,Sheng Wang,Wei Wei,Xing Lyu,Dariusz Plewczyński,Zhe Liu,Wei Liu,Yongjie Wei,Hákon Hákonarson,Qianghua Xia,Jin Li
标识
DOI:10.1016/j.jaci.2023.12.023
摘要
Background
CLEC16A intron 19 has been identified as a candidate locus for common variable immunodeficiency (CVID). Objectives
This study sought to elucidate the molecular mechanism by which variants at the CLEC16A intronic locus may contribute to the pathogenesis of CVID. Methods
The investigators performed fine-mapping of the CLEC16A locus in a CVID cohort, then deleted the candidate functional SNP in T-cell lines by the CRISPR-Cas9 technique and conducted RNA-sequencing to identify target gene(s). The interactions between the CLEC16A locus and its target genes were identified using circular chromosome conformation capture. The transcription factor complexes mediating the chromatin interactions were determined by proteomic approach. The molecular pathways regulated by the CLEC16A locus were examined by RNA-sequencing and reverse phase protein array. Results
This study showed that the CLEC16A locus is an enhancer regulating expression of multiple target genes including a distant gene ATF7IP2 through chromatin interactions. Distinct transcription factor complexes mediate the chromatin interactions in an allele-specific manner. Disruption of the CLEC16A locus affects the AKT signaling pathway, as well as the molecular response of CD4+ T cells to immune stimulation. Conclusions
Through multiomics and targeted experimental approaches, this study elucidated the underlying target genes and signaling pathways involved in the genetic association of CLEC16A with CVID, and highlighted plausible molecular targets for developing novel therapeutics.
科研通智能强力驱动
Strongly Powered by AbleSci AI