Variant-to-function analysis of the childhood obesity chr12q13 locus implicates rs7132908 as a causal variant within the 3' UTR of FAIM2.

IF 11.1 Q1 CELL BIOLOGY Cell genomics Pub Date : 2024-05-08 Epub Date: 2024-05-01 DOI:10.1016/j.xgen.2024.100556
Sheridan H Littleton, Khanh B Trang, Christina M Volpe, Kieona Cook, Nicole DeBruyne, Jean Ann Maguire, Mary Ann Weidekamp, Kenyaita M Hodge, Keith Boehm, Sumei Lu, Alessandra Chesi, Jonathan P Bradfield, James A Pippin, Stewart A Anderson, Andrew D Wells, Matthew C Pahl, Struan F A Grant
{"title":"Variant-to-function analysis of the childhood obesity chr12q13 locus implicates rs7132908 as a causal variant within the 3' UTR of FAIM2.","authors":"Sheridan H Littleton, Khanh B Trang, Christina M Volpe, Kieona Cook, Nicole DeBruyne, Jean Ann Maguire, Mary Ann Weidekamp, Kenyaita M Hodge, Keith Boehm, Sumei Lu, Alessandra Chesi, Jonathan P Bradfield, James A Pippin, Stewart A Anderson, Andrew D Wells, Matthew C Pahl, Struan F A Grant","doi":"10.1016/j.xgen.2024.100556","DOIUrl":null,"url":null,"abstract":"<p><p>The ch12q13 locus is among the most significant childhood obesity loci identified in genome-wide association studies. This locus resides in a non-coding region within FAIM2; thus, the underlying causal variant(s) presumably influence disease susceptibility via cis-regulation. We implicated rs7132908 as a putative causal variant by leveraging our in-house 3D genomic data and public domain datasets. Using a luciferase reporter assay, we observed allele-specific cis-regulatory activity of the immediate region harboring rs7132908. We generated isogenic human embryonic stem cell lines homozygous for either rs7132908 allele to assess changes in gene expression and chromatin accessibility throughout a differentiation to hypothalamic neurons, a key cell type known to regulate feeding behavior. The rs7132908 obesity risk allele influenced expression of FAIM2 and other genes and decreased the proportion of neurons produced by differentiation. We have functionally validated rs7132908 as a causal obesity variant that temporally regulates nearby effector genes and influences neurodevelopment and survival.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"100556"},"PeriodicalIF":11.1000,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11099382/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell genomics","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/j.xgen.2024.100556","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/5/1 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

The ch12q13 locus is among the most significant childhood obesity loci identified in genome-wide association studies. This locus resides in a non-coding region within FAIM2; thus, the underlying causal variant(s) presumably influence disease susceptibility via cis-regulation. We implicated rs7132908 as a putative causal variant by leveraging our in-house 3D genomic data and public domain datasets. Using a luciferase reporter assay, we observed allele-specific cis-regulatory activity of the immediate region harboring rs7132908. We generated isogenic human embryonic stem cell lines homozygous for either rs7132908 allele to assess changes in gene expression and chromatin accessibility throughout a differentiation to hypothalamic neurons, a key cell type known to regulate feeding behavior. The rs7132908 obesity risk allele influenced expression of FAIM2 and other genes and decreased the proportion of neurons produced by differentiation. We have functionally validated rs7132908 as a causal obesity variant that temporally regulates nearby effector genes and influences neurodevelopment and survival.

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
儿童肥胖症 chr12q13 位点的变异到功能分析显示,rs7132908 是 FAIM2 3' UTR 中的一个因果变异。
ch12q13位点是全基因组关联研究中发现的最重要的儿童肥胖位点之一。该位点位于 FAIM2 中的非编码区;因此,潜在的因果变异可能通过顺式调控影响疾病易感性。我们利用内部三维基因组数据和公共领域数据集,将 rs7132908 推测为一个因果变异体。通过荧光素酶报告实验,我们观察到了携带 rs7132908 的直接区域的等位基因特异性顺式调节活性。我们生成了rs7132908等位基因同源的人类胚胎干细胞系,以评估在向下丘脑神经元分化的整个过程中基因表达和染色质可及性的变化,下丘脑神经元是已知调节进食行为的关键细胞类型。rs7132908肥胖风险等位基因影响了FAIM2和其他基因的表达,并降低了分化产生的神经元比例。我们从功能上验证了 rs7132908 是肥胖症的因果变异基因,它能在时间上调节附近的效应基因,影响神经发育和存活。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
CiteScore
7.10
自引率
0.00%
发文量
0
期刊最新文献
A combined deep learning framework for mammalian m6A site prediction. Analysis of single-cell CRISPR perturbations indicates that enhancers predominantly act multiplicatively. Complex structural variation is prevalent and highly pathogenic in pediatric solid tumors. Gene regulatory network inference from CRISPR perturbations in primary CD4+ T cells elucidates the genomic basis of immune disease. Leveraging genomes to support conservation and bioeconomy policies in a megadiverse country.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1