Dissecting the role of retroelements and their variations in autoimmune diseases

• Project/Area Number: 21K19501
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 54:Internal medicine of the bio-information integration and related fields
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Kochi Yuta 東京医科歯科大学, 難治疾患研究所, 教授 (60415156)
• Project Period (FY): 2021-07-09 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2022: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2021: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: 自己免疫疾患 / ゲノムワイド関連解析 / ロングリードシークエンシング / レトロエレメント / 自然免疫刺激

Outline of Research at the Start

ゲノムワイド関連解析で多くの自己免疫疾患感受性遺伝子が明らかになったが、本研究では残された遺伝因子として内在性レトロエレメント配列の遺伝子多型に注目する。ロングリードシークエンス技術を用いて、日本人の不死化B細胞株における全ゲノムシークエンス(WG-seq)および網羅的発現解析(RNA-seq)を行う。これによって発現量に個人差をみとめるレトロエレメントRNAおよびその発現量を制御する遺伝子多型を網羅的に明らかにする。また、これらのレトロエレメント多型を関節リウマチ、全身性エリテマトーデス、炎症性筋炎でジェノタイピングし、自己免疫疾患発症に関わる多型を同定する。

Outline of Final Research Achievements

We aimed to clarify the role of retroelements in autoimmune diseases. First, we catalogued retroelement variations by long-read whole genome sequencing of Japanese B cell lines (n=27). We also performed Long-read RNA-seq of IFN-α-stimulated B cell lines and generated a catalog of 163,747 RNAs. Approximately 80% were novel RNAs, some of which were transcribed from unannotated loci including retroelements. We also identified genetic variations affecting the expression of these RNAs. We then integrated these data with genome-wide association study data and comprehensively identified those involved in autoimmune diseases.

Academic Significance and Societal Importance of the Research Achievements

本研究は、いまだ全貌が明らかになっていない自己免疫疾患の病因メカニズムについて、ゲノム上の未開拓領域であるレトロエレメントから迫るものである。本研究では、自己免疫疾患に関わるレトロエレメント由来のRNAを網羅的に明らかにしたが、これらの解析によって整備されたRNAカタログは、自己免疫疾患以外の様々な疾患の病因解明につながる貴重なリソースになると考えられる。

Research Products

• [Journal Article] Multi-ancestry genome-wide association analyses identify novel genetic mechanisms in rheumatoid arthritis (2022)
  • Author(s): Ishigaki K, Sakaue S, Terao C, Luo Y, Sonehara KvYamaguchi K, Amariuta T, Too CL, Laufer VA, Scott IC, Viatte S, Takahashi M, Ohmura K, Murasawa A, Hashimoto M, Ito H, ..., Okada Y et al.
  • Journal Title: Nature Genetics Volume: 54 Issue: 11 Pages: 1640-1651
  • DOI: 10.1038/s41588-022-01213-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Splicing QTL analysis focusing on coding sequences reveals mechanisms for disease susceptibility loci (2022)
  • Author(s): Yamaguchi Kensuke、Ishigaki Kazuyoshi、Suzuki Akari、Tsuchida Yumi、Tsuchiya Haruka、Sumitomo Shuji、Nagafuchi Yasuo、Miya Fuyuki、Tsunoda Tatsuhiko、Shoda Hirofumi、Fujio Keishi、Yamamoto Kazuhiko、Kochi Yuta
  • Journal Title: Nature Communications Volume: 13 Issue: 1 Pages: 4659-4659
  • DOI: 10.1038/s41467-022-32358-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Utility of tissue-specific gene expression scores for gene prioritization in Mendelian diseases (2022)
  • Author(s): Kato Daiki、Mitsuhashi Satomi、Miya Fuyuki、Saitoh Shinji、Okamoto Nobuhiko、Tsunoda Tatsuhiko、Kochi Yuta
  • Journal Title: Journal of Human Genetics Volume: 67 Issue: 12 Pages: 739-742
  • DOI: 10.1038/s10038-022-01071-8
  • Peer Reviewed
• [Journal Article] Biological insights into systemic lupus erythematosus through an immune cell-specific transcriptome-wide association study (2022)
  • Author(s): Yin Xianyong、Kim Kwangwoo、Tsutomu Takeuchi, et al.
  • Journal Title: Annals of the Rheumatic Diseases Volume: 81 Issue: 9 Pages: 1273-1280
  • DOI: 10.1136/annrheumdis-2022-222345
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Immune cell multiomics analysis reveals contribution of oxidative phosphorylation to B-cell functions and organ damage of lupus (2022)
  • Author(s): Takeshima Yusuke、Iwasaki Yukiko、Nakano Masahiro、Narushima Yuta、Ota Mineto、Nagafuchi Yasuo、Sumitomo Shuji、Okamura Tomohisa、Elkon Keith、Ishigaki Kazuyoshi、Suzuki Akari、Kochi Yuta、Yamamoto Kazuhiko、Fujio Keishi
  • Journal Title: Annals of the Rheumatic Diseases Volume: - Issue: 6 Pages: 845-853
  • DOI: 10.1136/annrheumdis-2021-221464
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Splicing QTL analysis focusing on coding sequences reveals pathogenicity of disease susceptibility loci (2022)
  • Author(s): Yamaguchi Kensuke、Ishigaki Kazuyoshi、Suzuki Akari、Tsuchida Yumi、Tsuchiya Haruka、Sumitomo Shuji、Nagafuchi Yasuo、Miya Fuyuki、Tsunoda Tatsuhiko、Hirofumi Shoda、Fujio Keishi、Yamamoto Kazuhiko、Kochi Yuta
  • Journal Title: bioRxiv Volume: -
  • DOI: 10.1101/2021.12.30.474578
• [Presentation] 多因子疾患におけるゲノム個別化医療 (2022)
  • Author(s): 高地雄太
  • Organizer: 第2回ゲノム医学研究会
  • Invited
• [Presentation] eQTL/sQTLから明らかにする多因子疾患の病態 (2021)
  • Author(s): 高地 雄太
  • Organizer: 日本オミックス医学会
  • Invited