Shared and distinct molecular effects of regulatory genetic variants provide insight into mechanisms of distal enhancer-promoter communication

Author:

Ray-Jones HelenORCID,Song Zeji,Haglund AlexanderORCID,Artemov PavelORCID,Della Rosa MonicaORCID,Burden FrancesORCID,Kreuzhuber RomanORCID,Litovskikh AnnaORCID,Tan Vanessa Xue Hui,Chan Lai Ting,Frontini MattiaORCID,Wallace ChrisORCID,Malysheva ValeriyaORCID,Bottolo LeonardoORCID,Vigorito ElenaORCID,Spivakov MikhailORCID

Abstract

AbstractTranscriptional enhancers regulate gene expression in time and space, commonly engaging in long-range chromosomal contacts with gene promoters. However, the relationship between enhancer activity, enhancer-promoter contacts and gene expression is not fully understood. Here, we leveraged human genetic variation as a “natural perturbation” to dissect this relationship, focusing on distal enhancers containing expression quantitative trait loci (eQTLs) – genetic variants linked to specific gene expression levels. We devised eQTL-Capture Hi-C to profile the chromosomal contacts of these loci globally and at high resolution in primary monocytes isolated from 34 donors, and generated chromatin accessibility and gene expression profiles from the same samples. Extending a Bayesian approach that considers both intra- and inter-individual variation, we detected 19 eQTLs linked to distinct promoter contacts, most of which also associated with enhancer accessibility and activity. Capitalising on these shared effects, we next employed a multi-modality Bayesian strategy, identifying hundreds of variants jointly associated with enhancer activity, connectivity, and gene expression. Many of these variants influenced the predicted binding of the architectural protein CTCF and the core myeloid transcription factors GABPA and SPI1; however, they typically did not perturb the canonical binding motifs of these factors. In contrast, one variant associated withPCK2promoter contact directly disrupted a CTCF binding motif and impacted the insulation of this promoter from downstream enhancers. Finally, many identified QTLs overlapped with disease susceptibility loci, underscoring the potential role of enhancer-promoter communication in mediating the pathological effects of non-coding genetic variation. Jointly, our findings suggest an inherent functional link between the activity and connectivity of enhancers with relevance for human disease, and highlight the role of genetically-determined chromatin boundaries in gene control.

Publisher

Cold Spring Harbor Laboratory

Cited by 1 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3