A novel pathogenesis of rheumatoid arthritis due to dysregulated super-enhancer in CD4-positive T cells

• Project/Area Number: 19K08925
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: University of Occupational and Environmental Health, Japan
• Principal Investigator: YAMAGATA KAORU 産業医科大学, 医学部, 講師 (80533786)
• Co-Investigator(Kenkyū-buntansha): 田中 良哉 産業医科大学, 医学部, 教授 (30248562)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 関節リウマチ / CD4陽性T細胞 / スーパーエンハンサー / UBASH3A / BACH2 / eRNA / ChIP / ubash3a / SNP / MED1 / 炎症 / 関節破壊

Outline of Research at the Start

関節リウマチ(RA)は滑膜炎症等を主病態とする。我々は、RA病態と関連し、CD4T細胞にてスーパーエンハンサー(SE;クラスターエンハンサーのため強力な転写活性を示す)制御を受け、高い発現を示す遺伝子UBASH3Aを見出した。しかし、T細胞受容体(TCR)シグナルの抑制因子UBASH3Aの発現制御機構、本病態形成への関与については不明である。本研究では、①RA患者群と対照群のCD4T細胞間においてUBASH3A発現量の比較、②エピジェネティック機構を介したSEによるUBASH3A発現制御、③UBASH3Aによる影響が強いCD4T細胞サブセットの特定等を行う。新規RA治療応用への展開を目指す。

Outline of Final Research Achievements

UBASH3A mRNA and protein expression was lower in CD4+ T cells from RA patients than in those from healthy donors. UBASH3A mRNA levels were reduced by eRNA_1 and eRNA_3 knockdown. In RA patients, BTB and CNC homology 2 (BACH2), the silencing transcription factor, accumulated at the UBASH3A loci in CD4+ T cells, whereas the SE-defining factor, mediator complex subunit 1 (MED1)/bromodomain 4 (BRD4), did not. However, opposite phenomena were observed in healthy donors. Although stimulation of TCRs expressed on CD4+ T cells from RA patients led to interleukin (IL)-6 production, UBASH3A over-expression significantly inhibited its production. In conclusion, we found that transcription of UBASH3A is suppressed via epigenetic regulation of SE in CD4+ T cells from RA patients. Decreased UBASH3A levels lead to excessive activation of TCR signaling, resulting in enhanced production of IL-6.

Academic Significance and Societal Importance of the Research Achievements

代表的な自己免疫疾患である関節リウマチ(RA)の患者においてT細胞が活性化しており、RA病態への機能的関与が予想されている。しかし、依然として病態の形成過程と進展過程を担う基盤について不明な点が多い。我々は、CD4+Ｔ細胞で高発現するUBASH3Aがリウマチで発現異常を示し、炎症と関わり、そしてRAの病態進展を担うことを解明した。

Research Products

• [Journal Article] Involvement of lncRNA IL21-AS1 in interleukin-2 and T follicular regulatory cell activation in systemic lupus erythematosus. (2021)
  • Author(s): Hao H, Nakayamada S, Ohkubo N, Yamagata K, Zhang M, Shan Y, Iwata S, Zhang T, Tanaka Y.
  • Journal Title: Arthritis Res Ther. Volume: 23 Issue: 1 Pages: 302-312
  • DOI: 10.1186/s13075-021-02682-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] T helper cells expressing fractalkine receptor and bearing T follicular helper 1-like cell functions in patients with IgG4-related disease. (2021)
  • Author(s): Inoue Y, Nakayamada S, Kubo S, Yamagata K, Sonomoto K, Iwata S, Miyazaki Y, Tanaka Y.
  • Journal Title: Rheumatology (Oxford) Volume: 未定 Issue: 9 Pages: 3854-3863
  • DOI: 10.1093/rheumatology/keab935
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] IL-2 drives conversion of T follicular helper cells to T follicular regulatory cells through transcriptional regulation in systemic lupus erythematosus. (2021)
  • Author(s): Hao H, Nakayamada S, Yamagata K, Ohkubo N, Iwata S, Inoue Y, Zhang M, Zhang T, Kanda Satoh Y, Shan Y, Otsuka T, Tanaka Y.
  • Journal Title: Arthritis Rheumatol. Volume: 73 Issue: 1 Pages: 132-142
  • DOI: 10.1002/art.41457
  • Peer Reviewed / Open Access
• [Journal Article] Human dendritic cell-derived osteoclasts with high bone resorption capacity and T cell stimulation ability. (2021)
  • Author(s): Narisawa M, Kubo S, Okada Y, Yamagata K, Nakayamada S, Sakata K, Yamaoka K, Tanaka Y.
  • Journal Title: Bone. Volume: 142 Pages: 115616-115616
  • DOI: 10.1016/j.bone.2020.115616
  • Peer Reviewed / Open Access
• [Journal Article] Critical Roles of Super-enhancers in the Pathogenesis of Autoimmune Diseases. (2020)
  • Author(s): Yamagata K, Nakayamada S, Tanaka Y.
  • Journal Title: Inflamm Regen. Volume: 40 Issue: 1 Pages: 16-16
  • DOI: 10.1186/s41232-020-00124-9
  • Peer Reviewed / Open Access
• [Journal Article] IL-23 drives expansion of Th17 cells through epigenetic regulation by signal transducer and activators of transcription 3 in lupus patients. (2020)
  • Author(s): Lee S, Nakayamada S, Kubo S, Yamagata K, Yoshinari H, Tanaka Yoshiya.
  • Journal Title: Rheumatology (Oxford). Volume: 59 Issue: 10 Pages: 3058-3069
  • DOI: 10.1093/rheumatology/keaa176
  • Peer Reviewed
• [Journal Article] Methionine commits cells to differentiate into plasmablasts through epigenetic regulation of BTB and CNC homolog 2 by the methyltransferase enhancer of zeste homolog 2. (2020)
  • Author(s): Zhang M, Iwata S, Hajime M, Ohkubo N, Todoroki Y, Miyata H, Ueno M, Hao H, Zhang T, Fan J, Nakayamada S, Yamagata K, Tanaka Y.
  • Journal Title: Arthritis Rheumatol. Volume: － Issue: 7 Pages: 1143-1153
  • DOI: 10.1002/art.41208
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Tumour necrosis factor alpha promotes secretion of 14-3-3η by inducing necroptosis in macrophages (2020)
  • Author(s): Trimova G, Yamagata K, Iwata S, Hirata S, Zhang T, Uemura F, Satoh M, Biln N, Nakayamada S, Maksymowych WP, Tanaka Y
  • Journal Title: Arthritis Res Ther Volume: 22 Issue: 1 Pages: 24-24
  • DOI: 10.1186/s13075-020-2110-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] IL-6 and sIL-6R induces STAT3-dependent differentiation of human VSMCs into osteoblast-like cells through JMJD2B-mediated histone demethylation of RUNX2. (2019)
  • Author(s): Kurozumi A, Nakano K, Yamagata K, Okada Y, Nakayamada S, Tanaka Y.
  • Journal Title: Bone Volume: 124 Pages: 53-61
  • DOI: 10.1016/j.bone.2019.04.006
  • Peer Reviewed
• [Journal Article] Glycolaldehyde-modified advanced glycation end-products inhibit differentiation of human monocytes into osteoclasts via upregulation of IL-10. (2019)
  • Author(s): Tanaka K, Yamagata K, Kubo S, Nakayamada S, Sakata K, Matsui T, Yamagishi SI, Okada Y, Tanaka Y.
  • Journal Title: Bone Volume: 128 Pages: 115034-115034
  • DOI: 10.1016/j.bone.2019.115034
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Soluble IL-6R promotes chondrogenic differentiation of mesenchymal stem cells to enhance the repair of articular cartilage defects using a rat model for rheumatoid arthritis. (2019)
  • Author(s): Yamagata K, Nakayamada S, Zhang T, Zhang X, Tanaka Y.
  • Journal Title: Clin Exp Rheumatol. Volume: －
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Emerging role of epigenetic dysregulation of ubash3a in the pathogenesis of rheumatoid arthritis (RA) (2020)
  • Author(s): Kaoru Yamagata, Shingo Nakayamada, Tong Zhang, Gulzhan Trimova, Phuong Anh Nguyen, Fumi Uemura, Ippei Miyagawa, Shigeru Iwata, Yoshiya Tanaka
  • Organizer: 第64回日本リウマチ学会
• [Presentation] 関節リウマチ患者のCD4陽性T細胞におけるubash3a遺伝子のエピジェネティック制御と炎症誘導機構の解明 (2020)
  • Author(s): 山形薫、中山田真吾、上村芙美、岩田慈、田中良哉
  • Organizer: 第41回日本炎症・再生医学会
• [Presentation] Massive in silico studies specified UBASH3A as a candidate pathogenic factor that is down-regulated in CD4+T cells of patients with rheumatoid arthritis (RA) (2019)
  • Author(s): Kaoru Yamagata, Shingo Nakayamada, Ippei Miyagawa, Fumi Uemura, Shigeru Iwata, Yoshiya Tanaka
  • Organizer: 第63回 日本リウマチ 学会
• [Presentation] スーパーエンハンサー(SE)による関節リウマチ(RA)感受性遺伝子UBASH3A のエピジェネティック制御機構の解明 (2019)
  • Author(s): 山形薫、中山田真吾、岩田慈、張童、トリモバグルズハン、グエンファンアン、上村芙美、宮川一平、加藤茂明、田中良哉
  • Organizer: 第5回日本骨免疫学会
• [Presentation] スーパーエンハンサーによる UBASH3A 遺伝子のエピジェネティック制御とその破綻による関節リウマチ (RA)病態形成 (2019)
  • Author(s): 山形薫、中山田真吾、岩田慈、Nguyen Phuong Anh、上村芙美、張童、Gulzhan Trimova、吉成紘子、宮川一平、加藤茂明、田中良哉
  • Organizer: 第40回日本炎症・再生医学会
• [Presentation] ナノファイバーを用いた間葉系幹細胞生体内移植の最適化とEBI3による制御 (2019)
  • Author(s): 山形薫、中山田真吾、張童、近藤 真弘、岩田慈、田中良哉
  • Organizer: 第37回日本骨代謝学会学術集会
  • Invited
• [Patent(Industrial Property Rights)] 軟骨組織修復方法 (2019)
  • Inventor(s): 田中良哉、山形薫、中山田真吾
  • Industrial Property Rights Holder: 田中良哉、山形薫、中山田真吾
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2016-119273
  • Filing Date: 2019
  • Acquisition Date: 2020