Whole-genome sequencing analysis using epigenetics databases to elucidate novel mechanisms of inherited arrhythmia syndromes
| Project/Area Number |
19K08566
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 53020:Cardiology-related
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| Research Institution | Nippon Medical School |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
大野 聖子 国立研究開発法人国立循環器病研究センター, 研究所, 部長 (20610025)
清水 渉 日本医科大学, 大学院医学研究科, 大学院教授 (50399606)
堀江 稔 滋賀医科大学, アジア疫学研究センター, 特任教授 (90183938)
相庭 武司 国立研究開発法人国立循環器病研究センター, 研究所, 部長 (40574348)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2021: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2019: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
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| Keywords | 遺伝性不整脈 / 心臓突然死 / ゲノム解析 / バイオインフォマティクス / エピジェネティクス / 全ゲノムシークエンス |
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| Outline of Research at the Start |
遺伝性不整脈は、若年で発症する心臓突然死の原因となる疾患群である。致死的な疾患であるにもかかわらず、代表的なQT延長症候群で3割、Brugada症候群を含む特発性心室細動では約8割にのぼる患者さんで遺伝子異常が同定されず、真の病因は未解明のままである。本研究の目的は、近年、加速度的に進歩している、全ゲノムシークエンスを中心とした遺伝子解析技術と複数のエピジェネティクス・データベースを組み合わせてバイオインフォマティクス解析を行い、遺伝性不整脈疾患のまだ明らかにされていない遺伝性と遺伝子基盤に基づいた病態メカニズムを解明し、早期診断法の開発と治療法の確立に寄与することである。
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| Outline of Final Research Achievements |
Epigenetic mechanism associated with inherited sudden death with sinus node dysfunction (SND) remains poorly understood. Here we show a family with SND segregating with the non-cording deletion associated with cis-regulatory elements (CREs) of the paired-like homeodomain transcription factor 2 (PITX2). We applied 30x whole-genome sequencing to a family presenting patients with SND and identified a 15-kilobase-pairs deletion on chromosome 4q25. This non-coding deletion was located in the intergenic region between PITX2 and ANK2 and contained a binding motif of CCCTC-binding factor (CTCF). Bioinformatics analysis with several epigenetic databases clarified a possible regulatory function of the intergenic region. We concluded that disruption of CTCF-mediated genomic interaction between PITX2 and CREs caused overexpression of PITX2 in patients’ induced pluripotent stem cells (iPSC) derived nodal cells and a SND phenotype in a deletion mouse model.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究は、ヒストン修飾情報、転写因子結合部位（シストローム）、ゲノム構造化解析を含むエピジェネティクス・データベースを用いた包括的バイオインフォマティクス技術により、遺伝性不整脈疾患の全ゲノムシークエンスデータからタンパク・アミノ酸に翻訳されるコードDNA領域のみならず非コードDNA領域に局在する調節因子の異常を検出することで、遺伝性不整脈疾患の新規発症機序を解明した初めての研究である。本解析法を用いることで全ゲノムシークエンスの真の利点を生かすことが可能となる。
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Report
(4 results)
Research Products
(36 results)
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[Journal Article] JCS/JHRS 2020 Guideline on Pharmacotherapy of Cardiac Arrhythmias2022
Author(s)
Ono K, Iwasaki YK, Akao M, Makiyama T, Maruyama M, Miake J, Muraji S, Murata H, Morita N, Yokoshiki H, Yoshioka K, Yodogawa K, Inoue H, Okumura K, Kimura T, Tsutsui H, Shimizu W
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Journal Title
Circulation Journal
Volume: 86
Issue: 11
Pages: 1790-1924
DOI
ISSN
1346-9843, 1347-4820
Year and Date
2022-10-25
Related Report
Peer Reviewed / Open Access
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[Journal Article] Long-term prognosis of patients with J-wave syndrome.2020
Author(s)
Kamakura T, Shinohara T, Yodogawa K, Murakoshi N, Morita H, Takahashi N, Inden Y, Shimizu W, Nogami A, Horie M, Aiba T, Kusano K.
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Journal Title
Heart
Volume: 106
Issue: 4
Pages: 299-306
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Linking the heart and the brain: Neurodevelopmental disorders in patients with catecholaminergic polymorphic ventricular tachycardia2019
Author(s)
Lieve KVV, Verhagen JMA, Wei J, Bos JM, van der Werf C, Roses I Noguer F, Mancini GMS, Guo W, Wang R, van den Heuvel F, Frohn-Mulder IME, Shimizu W, Nogami A, Horigome H, Roberts JD, Leenhardt A, Crijns HJG, Blank AC, Aiba T, Wiesfeld ACP, Blom NA, Sumitomo N, Till J, Ackerman MJ, Chen SRW, van de Laar IMBH, Wilde AAM
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Journal Title
Heart Rhythm
Volume: 16(2)
Issue: 2
Pages: 220-228
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Presentation] A novel mechanism of sinus node dysfunction: intergenic deletion between PITX2 and ANK2 disrupts chromatin structure in pacemaker cell differentiation2019
Author(s)
Murata H, Shimizu W, Lindenbaum P, Le Scouarnec S, Baron E, Rajalu A, Kyndt1 F, Deleuze JF, Le Marec H, Probst V, Redon R and Schot JJ
Organizer
第40回米国不整脈学会(HRS 2019)
Related Report
Int'l Joint Research
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[Presentation] A novel mechanism of sinus node dysfunction: intergenic deletion between PITX2 and ANK2 disrupts chromatin structure in pacemaker cell differentiation2019
Author(s)
Murata H, Shimizu W, Lindenbaum P, Le Scouarnec S, Baron E, Rajalu A, Kyndt1 F, Deleuze JF, Le Marec H, Probst V, Redon R and Schot JJ
Organizer
第66回日本不整脈心電学会学術大会
Related Report
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[Presentation] A novel mechanism of sinus node dysfunction: intergenic deletion between PITX2 and ANK2 disrupts chromatin structure in pacemaker cell differentiation2019
Author(s)
Murata H, Shimizu W, Lindenbaum P, Le Scouarnec S, Baron E, Rajalu A, Kyndt1 F, Deleuze JF, Le Marec H, Probst V, Redon R and Schot JJ
Organizer
European Society of Cardiology Congress2019
Related Report
Int'l Joint Research
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