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Article: High-throughput identification of regulatory elements and functional assays to uncover susceptibility genes for nasopharyngeal carcinoma

TitleHigh-throughput identification of regulatory elements and functional assays to uncover susceptibility genes for nasopharyngeal carcinoma
Authors
Keywordscis-regulatory elements
functional profiling
genome-wide association study
nasopharyngeal carcinoma
Issue Date6-Jul-2023
PublisherCell Press
Citation
American Journal of Human Genetics, 2023, v. 110, n. 7, p. 1162-1176 How to Cite?
Abstract

Large-scale genetic association studies have identified multiple susceptibility loci for nasopharyngeal carcinoma (NPC), but the underlying biological mechanisms remain to be explored. To gain insights into the genetic etiology of NPC, we conducted a follow-up study encompassing 6,907 cases and 10,472 controls and identified two additional NPC susceptibility loci, 9q22.33 (rs1867277; OR = 0.74, 95% CI = 0.68–0.81, p = 3.08 × 10−11) and 17q12 (rs226241; OR = 1.42, 95% CI = 1.26–1.60, p = 1.62 × 10−8). The two additional loci, together with two previously reported genome-wide significant loci, 5p15.33 and 9p21.3, were investigated by high-throughput sequencing for chromatin accessibility, histone modification, and promoter capture Hi-C (PCHi-C) profiling. Using luciferase reporter assays and CRISPR interference (CRISPRi) to validate the functional profiling, we identified PHF2 at locus 9q22.33 as a susceptibility gene. PHF2 encodes a histone demethylase and acts as a tumor suppressor. The risk alleles of the functional SNPs reduced the expression of the target gene PHF2 by inhibiting the enhancer activity of its long-range (4.3 Mb) cis-regulatory element, which promoted proliferation of NPC cells. In addition, we identified CDKN2B-AS1 as a susceptibility gene at locus 9p21.3, and the NPC risk allele of the functional SNP rs2069418 promoted the expression of CDKN2B-AS1 by increasing its enhancer activity. The overexpression of CDKN2B-AS1 facilitated proliferation of NPC cells. In summary, we identified functional SNPs and NPC susceptibility genes, which provides additional explanations for the genetic association signals and helps to uncover the underlying genetic etiology of NPC development.


Persistent Identifierhttp://hdl.handle.net/10722/331552
ISSN
2023 Impact Factor: 8.1
2023 SCImago Journal Rankings: 4.516
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorWang, TM-
dc.contributor.authorXiao, RW-
dc.contributor.authorHe, YQ-
dc.contributor.authorZhang, WL-
dc.contributor.authorDiao, H-
dc.contributor.authorTang, MZ-
dc.contributor.authorMai, ZM-
dc.contributor.authorXue, WQ-
dc.contributor.authorYang, DW-
dc.contributor.authorDeng, CM-
dc.contributor.authorLiao, Y-
dc.contributor.authorZhou, T-
dc.contributor.authorLi, DH-
dc.contributor.authorWu, YX-
dc.contributor.authorChen, XY-
dc.contributor.authorZhang, JB-
dc.contributor.authorLi, XZ-
dc.contributor.authorZhang, PF-
dc.contributor.authorZheng, XH-
dc.contributor.authorZhang, SD-
dc.contributor.authorHu, YZ-
dc.contributor.authorCai, YL-
dc.contributor.authorZheng, YM-
dc.contributor.authorZhang, Z-
dc.contributor.authorZhou, YF-
dc.contributor.authorJin, GF-
dc.contributor.authorBei, JX-
dc.contributor.authorMai, HQ-
dc.contributor.authorSun, Y-
dc.contributor.authorMa, J-
dc.contributor.authorHu, ZB-
dc.contributor.authorLiu, JJ-
dc.contributor.authorLung, ML-
dc.contributor.authorAdami, HO-
dc.contributor.authorYe, WM-
dc.contributor.authorLam, TH-
dc.contributor.authorShen, HB-
dc.contributor.authorJia, WH-
dc.date.accessioned2023-09-21T06:56:52Z-
dc.date.available2023-09-21T06:56:52Z-
dc.date.issued2023-07-06-
dc.identifier.citationAmerican Journal of Human Genetics, 2023, v. 110, n. 7, p. 1162-1176-
dc.identifier.issn0002-9297-
dc.identifier.urihttp://hdl.handle.net/10722/331552-
dc.description.abstract<p>Large-scale genetic association studies have identified multiple susceptibility loci for nasopharyngeal carcinoma (NPC), but the underlying biological mechanisms remain to be explored. To gain insights into the genetic etiology of NPC, we conducted a follow-up study encompassing 6,907 cases and 10,472 controls and identified two additional NPC susceptibility loci, 9q22.33 (rs1867277; OR = 0.74, 95% CI = 0.68–0.81, p = 3.08 × 10<sup>−11</sup>) and 17q12 (rs226241; OR = 1.42, 95% CI = 1.26–1.60, p = 1.62 × 10<sup>−8</sup>). The two additional loci, together with two previously reported genome-wide significant loci, 5p15.33 and 9p21.3, were investigated by high-throughput sequencing for chromatin accessibility, histone modification, and promoter capture Hi-C (PCHi-C) profiling. Using luciferase reporter assays and CRISPR interference (CRISPRi) to validate the functional profiling, we identified <em>PHF2</em> at locus 9q22.33 as a susceptibility gene. <em>PHF2</em> encodes a histone demethylase and acts as a tumor suppressor. The risk alleles of the functional SNPs reduced the expression of the target gene <em>PHF2</em> by inhibiting the enhancer activity of its long-range (4.3 Mb) <em>cis</em>-regulatory element, which promoted proliferation of NPC cells. In addition, we identified <em>CDKN2B-AS1</em> as a susceptibility gene at locus 9p21.3, and the NPC risk allele of the functional SNP rs2069418 promoted the expression of <em>CDKN2B-AS1</em> by increasing its enhancer activity. The overexpression of <em>CDKN2B-AS1</em> facilitated proliferation of NPC cells. In summary, we identified functional SNPs and NPC susceptibility genes, which provides additional explanations for the genetic association signals and helps to uncover the underlying genetic etiology of NPC development.</p>-
dc.languageeng-
dc.publisherCell Press-
dc.relation.ispartofAmerican Journal of Human Genetics-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectcis-regulatory elements-
dc.subjectfunctional profiling-
dc.subjectgenome-wide association study-
dc.subjectnasopharyngeal carcinoma-
dc.titleHigh-throughput identification of regulatory elements and functional assays to uncover susceptibility genes for nasopharyngeal carcinoma-
dc.typeArticle-
dc.identifier.doi10.1016/j.ajhg.2023.06.003-
dc.identifier.scopuseid_2-s2.0-85164253489-
dc.identifier.volume110-
dc.identifier.issue7-
dc.identifier.spage1162-
dc.identifier.epage1176-
dc.identifier.eissn1537-6605-
dc.identifier.isiWOS:001040419300001-
dc.identifier.issnl0002-9297-

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