The role(s) of UTX, histone demethylase for H3K27me3, in B cell regulatory mechanisms and autoimmune disease pathogenesis

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K17918
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: Tokyo Women's Medical University
• Principal Investigator: Sera Yasuyuki 東京女子医科大学, 医学部, 助教 (40836532)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: UTX / B細胞 / B-1細胞 / 辺縁帯B細胞 / 自己免疫疾患 / エピジェネティクス

Outline of Final Research Achievements

UTX is a demethylase for trimethylated 27 on histone H3. The patients with Kabuki syndrome have congenital loss-of-function mutations in UTX. Since patients with this disease frequently develop autoimmune diseases, it is expected that the deletion of UTX in immune cells contributes to their pathogenesis, but the details are not clear. To investigate the role(s) of UTX in B cell regulatory mechanisms and autoimmune diseases, we generated B cell-specific UTX-deficient mice. This mice showed various abnormalities in B cell subsets of the innate immune system, such as B-1 cells and marginal zone B cells, which are involved in the pathogenesis of autoimmune diseases. Transcriptome analysis of those cells suggested that BCR signaling might be attenuated.
The results of this study may provide a basis for elucidating the pathogenesis of autoimmune diseases caused by congenital UTX deletion or epigenetic deregulation and for developing therapeutic strategies.

Free Research Field

実験動物

Academic Significance and Societal Importance of the Research Achievements

エピジェネティクスは、クロマチン修飾による、塩基配列によらない可逆的な遺伝子発現制御機構であり、環境変化に感受性を持つ。自己免疫疾患の発症機構には、遺伝的要因に加えて環境要因が発症に重要なことから、エピジェネティクスに関心が寄せられている。本研究の成果は、B細胞のエピジェネティクスによる制御機構の一端を明らかにするとともに、先天性のUTX欠失が原因の歌舞伎症候群でみられる自己免疫疾患や、共通の病態をもつ自己免疫疾患の発症機構解明と治療法開発につながる可能性がある。