Asthma-associated genetic variants induce IL33 differential expression through an enhancer-blocking regulatory region.
Asthma-associated genetic variants induce IL33 differential expression through an enhancer-blocking regulatory region.
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DOI：
10.1038/s41467-021-26347-z
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发表时间：
2021-10-21
影响因子：
16.6
通讯作者：
Nóbrega MA
中科院分区：
文献类型：
--
作者：
Aneas I;Decker DC;Howard CL;Sobreira DR;Sakabe NJ;Blaine KM;Stein MM;Hrusch CL;Montefiori LE;Tena J;Magnaye KM;Clay SM;Gern JE;Jackson DJ;Altman MC;Naureckas ET;Hogarth DK;White SR;Gomez-Skarmeta JL;Schoetler N;Ober C;Sperling AI;Nóbrega MA
全基因组关联研究 (GWAS) 表明 IL33 位点与哮喘有关，但其潜在机制仍不清楚。在这里，我们在 GWAS 定义的片段中鉴定了一个 5 kb 的区域，该区域在体内和体外充当增强子阻断元件。染色质构象捕获表明，这个 5 kb 区域与 IL33 启动子形成环，可能调节其表达。我们发现，位于 5kb 区域内的哮喘相关单核苷酸多态性 (SNP) rs1888909 与人气道上皮细胞中的 IL33 基因表达和人血浆中的 IL-33 蛋白表达相关，可能是通过 OCT-1 (POU2F1) 与哮喘风险等位基因的差异结合来实现的。我们的数据表明，IL33 位点的哮喘相关变异介导等位基因特异性调节活性和 IL33 表达，提供了调节性 SNP 导致哮喘遗传风险的机制。哮喘的易感性和症状的严重程度是由许多不同的基因组区域调节的。在这里，作者描述了 5kb 调控区域的特征，并证明了 IL33 的遗传和拓扑调控以及与不同人类群体中疾病的关联。
Genome-wide association studies (GWAS) have implicated the IL33 locus in asthma, but the underlying mechanisms remain unclear. Here, we identify a 5 kb region within the GWAS-defined segment that acts as an enhancer-blocking element in vivo and in vitro. Chromatin conformation capture showed that this 5 kb region loops to the IL33 promoter, potentially regulating its expression. We show that the asthma-associated single nucleotide polymorphism (SNP) rs1888909, located within the 5 kb region, is associated with IL33 gene expression in human airway epithelial cells and IL-33 protein expression in human plasma, potentially through differential binding of OCT-1 (POU2F1) to the asthma-risk allele. Our data demonstrate that asthma-associated variants at the IL33 locus mediate allele-specific regulatory activity and IL33 expression, providing a mechanism through which a regulatory SNP contributes to genetic risk of asthma. Susceptibility to asthma and severity of symptoms are regulated by a number of different genomic regions. Here the authors characterise a 5kb regulatory region and demonstrate genetic and topological regulation of IL33 and association with disease in different human cohorts.
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影响因子：
9.8
作者：
ENCODE Project Consortium
通讯作者：
ENCODE Project Consortium
影响因子：
5.9
作者：
Helling BA;Sobreira DR;Hansen GT;Sakabe NJ;Luo K;Billstrand C;Laxman B;Nicolae RI;Nicolae DL;Bochkov YA;Gern JE;Nobrega MA;White SR;Ober C
通讯作者：
Ober C
影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
影响因子：
3.7
作者：
Kim K;Kim N;Lee GR
通讯作者：
Lee GR
影响因子：
30.8
作者：
Demenais F;Margaritte-Jeannin P;Barnes KC;Cookson WOC;Altmüller J;Ang W;Barr RG;Beaty TH;Becker AB;Beilby J;Bisgaard H;Bjornsdottir US;Bleecker E;Bønnelykke K;Boomsma DI;Bouzigon E;Brightling CE;Brossard M;Brusselle GG;Burchard E;Burkart KM;Bush A;Chan-Yeung M;Chung KF;Couto Alves A;Curtin JA;Custovic A;Daley D;de Jongste JC;Del-Rio-Navarro BE;Donohue KM;Duijts L;Eng C;Eriksson JG;Farrall M;Fedorova Y;Feenstra B;Ferreira MA;Australian Asthma Genetics Consortium (AAGC) collaborators;Freidin MB;Gajdos Z;Gauderman J;Gehring U;Geller F;Genuneit J;Gharib SA;Gilliland F;Granell R;Graves PE;Gudbjartsson DF;Haahtela T;Heckbert SR;Heederik D;Heinrich J;Heliövaara M;Henderson J;Himes BE;Hirose H;Hirschhorn JN;Hofman A;Holt P;Hottenga J;Hudson TJ;Hui J;Imboden M;Ivanov V;Jaddoe VWV;James A;Janson C;Jarvelin MR;Jarvis D;Jones G;Jonsdottir I;Jousilahti P;Kabesch M;Kähönen M;Kantor DB;Karunas AS;Khusnutdinova E;Koppelman GH;Kozyrskyj AL;Kreiner E;Kubo M;Kumar R;Kumar A;Kuokkanen M;Lahousse L;Laitinen T;Laprise C;Lathrop M;Lau S;Lee YA;Lehtimäki T;Letort S;Levin AM;Li G;Liang L;Loehr LR;London SJ;Loth DW;Manichaikul A;Marenholz I;Martinez FJ;Matheson MC;Mathias RA;Matsumoto K;Mbarek H;McArdle WL;Melbye M;Melén E;Meyers D;Michel S;Mohamdi H;Musk AW;Myers RA;Nieuwenhuis MAE;Noguchi E;O'Connor GT;Ogorodova LM;Palmer CD;Palotie A;Park JE;Pennell CE;Pershagen G;Polonikov A;Postma DS;Probst-Hensch N;Puzyrev VP;Raby BA;Raitakari OT;Ramasamy A;Rich SS;Robertson CF;Romieu I;Salam MT;Salomaa V;Schlünssen V;Scott R;Selivanova PA;Sigsgaard T;Simpson A;Siroux V;Smith LJ;Solodilova M;Standl M;Stefansson K;Strachan DP;Stricker BH;Takahashi A;Thompson PJ;Thorleifsson G;Thorsteinsdottir U;Tiesler CMT;Torgerson DG;Tsunoda T;Uitterlinden AG;van der Valk RJP;Vaysse A;Vedantam S;von Berg A;von Mutius E;Vonk JM;Waage J;Wareham NJ;Weiss ST;White WB;Wickman M;Widén E;Willemsen G;Williams LK;Wouters IM;Yang JJ;Zhao JH;Moffatt MF;Ober C;Nicolae DL
通讯作者：
Nicolae DL