Allelic Imbalance in Regulation of ANRIL through Chromatin Interaction at 9p21 Endometriosis Risk Locus

• Project/Area Number: 15H02373
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Medical genome science
• Research Institution: National Institute of Genetics
• Principal Investigator: Inoue Ituro 国立遺伝学研究所, 総合遺伝研究系, 教授 (00192500)
• Co-Investigator(Kenkyū-buntansha): 佐藤 健人 東海大学, 医学部, 准教授 (50235363) ; 細道 一善 金沢大学, 医学系, 准教授 (50420948)
• Co-Investigator(Renkei-kenkyūsha): ENOMOTO Takayuki 新潟大学, 医歯学系, 教授 (90283754) ; AKIRA Shigeo 日本医科大学, 医学部, 教授 (40231849)
• Research Collaborator: NAKAOKA Hirofumi 国立遺伝学研究所, 総合遺伝研究系, 助教 (70611193)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥43,680,000 (Direct Cost: ¥33,600,000、Indirect Cost: ¥10,080,000); Fiscal Year 2017: ¥10,660,000 (Direct Cost: ¥8,200,000、Indirect Cost: ¥2,460,000); Fiscal Year 2016: ¥10,530,000 (Direct Cost: ¥8,100,000、Indirect Cost: ¥2,430,000); Fiscal Year 2015: ¥22,490,000 (Direct Cost: ¥17,300,000、Indirect Cost: ¥5,190,000)
• Keywords: 子宮内膜症 / アレル優位性 / エンハンサー活性 / クロマチン高次構造 / 疾患関連遺伝子 / 遺伝学

Outline of Final Research Achievements

We explored regulatory mechanism of a SNP on chromosome 9p21 associated with endometriosis by leveraging“allele-specific”functional genomic approaches. By re-sequencing 1.29 Mb of 9p21 region and scrutinizing DNase-seq data from the ENCODE project, we prioritized rs17761446 as a candidate functional variant that was in perfect linkage disequilibrium with the GWAS SNP (rs10965235) and located on DNase I hypersensitive site. Chromosome conformation capture followed by high-throughput sequencing revealed that the protective G allele of rs17761446 exerted stronger chromatin interaction with ANRIL promoter. The protective allele exhibited preferential binding affinities to TCF7L2 and EP300 by chromatin immunoprecipitation (ChIP) analyses. The allele specific expression analysis for eutopic endometrial tissues and endometrial carcinoma cell lines showed that rs17761446 was a cis-regulatory variant where G allele was associated with increased ANRIL.

Research Products

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• [Journal Article] AMBRA1 is involved in T cell receptor-mediated metabolic reprogramming through an ATG7-independent pathway (2017)
  • Author(s): Akatsuka Hisako、Kuga Shuhei、Masuhara Kaori、Davaadorj Odontuya、Okada Chisa、Iida Yumi、Okada Yoshinori、Fukunishi Nahoko、Suzuki Takahiro、Hosomichi Kazuyoshi、Ohtsuka Masato、Tanaka Masafumi、Inoue Ituro、Kimura Minoru、Sato Takehito
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• [Journal Article] Identification of a novel variant of the RET proto-oncogene in a novel family with Hirschsprung’s disease (2017)
  • Author(s): Kawano Takafumi、Hosomichi Kazuyoshi、Inoue Ituro、Shimono Ryuichi、Onishi Shun、Nakame Kazuhiko、Kaji Tatsuru、Matsufuji Hiroshi、Ieiri Satoshi
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• [Journal Article] Systematic identification and characterization of regulatory elements derived from human endogenous retroviruses (2017)
  • Author(s): Ito J, Sugimoto R, Nakaoka H, Yamada S, Kimura T, Hayano T, Inoue I.
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• [Journal Article] GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes. (2017)
  • Author(s): Nakayama A, Nakaoka H, Yamamoto K, Sakiyama M, Shaukat A, Toyoda Y, Okada Y, Ohkawa Y,他39名
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• [Journal Article] Comprehensive microbiome analysis of tonsillar crypts in IgA nephropathy (2017)
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  • DOI: 10.1093/ndt/gfw343
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• [Journal Article] A partial nuclear genome of the Jomons who lived 3000 years ago in Fukushima, Japan. (2017)
  • Author(s): Kanzawa-Kiriyama H, Kryukov K, Jinam TA, Hosomichi K, Saso A, Suwa G, Ueda S, Yoneda M, Tajima A, Shinoda KI, Inoue I, Saitou N. A partial nuclear genome of the Jomons who lived 3000 years ago in Fukushima, Japan
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• [Journal Article] Rapid and cost-effective high-throughput sequencing for identification of germline mutations of BRCA1 and BRCA2 (2017)
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• [Journal Article] Comprehensive genetic exploration of selective tooth agenesis of mandibular incisors by exome sequencing (2017)
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• [Journal Article] Structure and evolution of the filaggrin gene repeated region in primates (2017)
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• [Journal Article] Germline Variants of Prostate Cancer in Japanese Families (2017)
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  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 25360-25360
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• [Journal Article] Allelic Imbalance in Regulation of ANRIL through Chromatin Interaction at 9p21 Endometriosis Risk Locus. (2016)
  • Author(s): Nakaoka H, Gurumurthy A, Hayano T, Ahmadloo S, Omer WH, Yoshihara K, Yamamoto A, Kurose K, Enomoto T, Akira S, Hosomichi K,, Inoue I.
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  • Author(s): 中岡博史、井ノ上逸朗
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• [Journal Article] Novel kinase fusion transcripts found in endometrial cancer. (2015)
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• [Journal Article] The impact of next-generation sequencing technologies on HLA research. (2015)
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  • NAID: 40020655134
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• [Journal Article] Distribution of HLA haplotypes across Japanese Archipelago: similarity, difference and admixture. (2015)
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  • Peer Reviewed
• [Journal Article] Unique characteristics of the Ainu population in Northern Japan (2015)
  • Author(s): Jinam TA, Kanzawa-Kiriyama H, Inoue I, Tokunaga K, Omoto K, Saitou N
  • Journal Title: Journal of Human Genetics Volume: 60 Issue: 10 Pages: 565-571
  • DOI: 10.1038/jhg.2015.79
  • NAID: 40020621361
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• [Journal Article] Aggregation of rare/low-frequency variants of the mitochondria respiratory chain-related proteins in rheumatoid arthritis patients. (2015)
  • Author(s): Mitsunaga S, Hosomichi K, Okudaira Y, Nakaoka H, Suzuki Y, Kuwana M, Sato S, Kaneko Y, Homma Y, Oka A, Shiina T, Inoko H, Inoue I.
  • Journal Title: J Hum Genet Volume: 60 Issue: 8 Pages: 449-454
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  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 体細胞変異からの子宮内膜症の成因 その3 逆行仮説の検証 (2017)
  • Author(s): 井ノ上 逸朗
  • Organizer: 日本人類遺伝学会 第62回大会
• [Presentation] Allelic imbalance in regulation of ANRIL through chromatin interaction at 9p21 endometriosis risk locus. (2016)
  • Author(s): Nakaoka H, Gurumurthy A, Hayano T, Ahmadloo S, Omer W, Hata C, Kimura T, Hosomichi K, Inoue I.
  • Organizer: The American Society of Human Genetics 66th Annual Meeting
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2016-10-18
  • Int'l Joint Research
• [Presentation] Systematic identification and characterization of regulatory elements derived from human endogenous retroviruses. (2016)
  • Author(s): Ito J, Yamada S, Sugimoto R, Kimura T, Nakaoka H, Inoue I.
  • Organizer: The American Society of Human Genetics 66th Annual Meeting
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2016-10-18
  • Int'l Joint Research
• [Presentation] Allelic imbalance in regulation of ANRIL through chromatin interaction at 9p21 endometriosis risk locus (2016)
  • Author(s): Hirofumi Nakaoka
  • Organizer: The 13th International Congress of Human Genetics
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2016-04-05
  • Int'l Joint Research
• [Presentation] Evolution of the ‘fused’ gene family across primates. (2016)
  • Author(s): Nakaoka H, Romero V, Inoue I, Hosomichi K.
  • Organizer: The 13th International Congress of Human Genetics.
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2016-04-03
  • Int'l Joint Research
• [Presentation] Allelic imbalance in regulation of ANRIL through chromatin interaction at 9p21 endometriosis risk locus. (2016)
  • Author(s): Nakaoka H, Gurumurthy A, Hayano T, Ahmadloo S, Omer W, Hosomichi K, Inoue I.
  • Organizer: The 13th International Congress of Human Genetics.
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2016-04-03
  • Int'l Joint Research