The roles of histone demethylases in transcriptional process involved in cell differentiation

• Project/Area Number: 19K06492
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 43010:Molecular biology-related
• Research Institution: Keio University
• Principal Investigator: Akiyama Tomohiko 慶應義塾大学, 医学部(信濃町), 講師 (20570691)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 多能性 / 転写制御因子 / 配置制御 / 多能性幹細胞 / 分化制御 / ヒストン脱メチル化酵素 / ヒト多能性幹細胞 / 転写調節 / クロマチン構造

Outline of Research at the Start

多能性幹細胞において分化に関わる遺伝子はヒストンH3K27のメチル化修飾（H3K27me3）によって抑制されており、メチル化消去に伴い、発現が開始され分化プログラムが起動する。H3K27me3を取り除く脱メチル化酵素遺伝子としてJMJD3とUTXが存在するが、これまでその役割の違いについては殆んど明らかにされていなかった。本研究では、同じ基質を触媒する2つの酵素JMJD3とUTXが別々の役割を果たし、両者の相互作用によって遺伝子発現が調節されるという仮説を提唱し、転写制御プロセスの新たなエピジェネティック機構を解明する。

Outline of Final Research Achievements

In this study, we found that UTX regulates pluripotency of human ES cells by the demethylase activity independent pathway. Therefore, we focused on UTY, a homolog of UTX, which is encoded on the Y chromosome. UTY is evolutionarily mutated in the enzyme activity and has no demethylation function. When both UTX and UTY were deleted, abnormalities in gene expression were observed globally in undifferentiated ES cells and differentiated cells. Furthermore, the localization of transcription factors that bind to enhancer regions was altered in thousands of locations. These results indicate that UTX and UTY regulate transcription factor positioning in a demethylase-independent manner and are involved in the regulation of ES cell differentiation.

Academic Significance and Societal Importance of the Research Achievements

本研究では、ヒト多能性幹細胞における転写制御因子のゲノム上の配置を制御する因子を同定した。これらの結果は、ヒト発生の分子機構を明らかにしただけでなく、細胞分化誘導技術の開発において有用な知見として期待される。

Research Products

• [Journal Article] Synthetic mRNA‐based differentiation method enables early detection of Parkinson's phenotypes in neurons derived from Gaucher disease‐induced pluripotent stem cells (2020)
  • Author(s): Akiyama Tomohiko（責任著者）、Sato Saeko、Ko Shigeru B. H.、Sano Osamu、Sato Sho、Saito Masayo、Nagai Hiroaki、Ko Minoru S. H.、Iwata Hidehisa
  • Journal Title: STEM CELLS Translational Medicine Volume: 10 Issue: 4 Pages: 572-581
  • DOI: 10.1002/sctm.20-0302
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Fatty Acid Synthesis Is Indispensable for Survival of Human Pluripotent Stem Cells (2020)
  • Author(s): Sho Tanosaki, Shugo Tohyama, Jun Fujita, Hiroki Nakanishi, Takayo Ohto-Nakanishi, Tomohiko Akiyama, Yuika Morita, Yoshikazu Kishino, Marina Okada, Hidenori Tani, Yusuke Soma, Kazuaki Nakajima, Hideaki Kanazawa, Masahiro Sugimoto, Minoru S.H. Ko, Makoto Suematsu, Keiichi Fukuda
  • Journal Title: iScience Volume: 23 Issue: 9 Pages: 101535-101535
  • DOI: 10.1016/j.isci.2020.101535
  • Peer Reviewed / Open Access
• [Journal Article] Generation and Profiling of 2,135 Human ESC Lines for the Systematic Analyses of Cell States Perturbed by Inducing Single Transcription Factors (2020)
  • Author(s): Nakatake Y、Ko S B.H.、Sharov A A.、Wakabayashi S、Murakami M、Sakota M、Chikazawa N、Ookura C、Sato S、Ito N、Ishikawa-Hirayama M、Mak Siu S、Jakt Lars M、Ueno T、Hiratsuka K、Matsushita M、Goparaju S K、Akiyama T、Ishiguro K、Oda M、Gouda N、Umezawa A、Akutsu H、Nishimura K、Matoba R、Ohara O、Ko M S.H.
  • Journal Title: Cell Reports Volume: 31 Issue: 7 Pages: 107655-107655
  • DOI: 10.1016/j.celrep.2020.107655
  • Peer Reviewed / Open Access / Int'l Joint Research