Mechanisms underlying epigenome regulation by chromatin modifications during stem cell differentiation

2014 Fiscal Year Final Research Report

• Project Area: Molecular mechanisms of cell fate determination in the cells that undergo stepwise differentiation to multiple pathways
• Project/Area Number: 22118003
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Nagoya City University
• Principal Investigator: NAKANISHI Makoto 名古屋市立大学, 医学(系)研究科(研究院), 教授 (40217774)
• Co-Investigator(Kenkyū-buntansha): YOKOYAMA Akihiko 京都大学, 医学研究科, 特定准教授 (10506710)
• Project Period (FY): 2010-04-01 – 2015-03-31
• Keywords: ゲノム / シグナル伝達 / 発現抑制 / 発生・分化

Outline of Final Research Achievements

1. Molecular mechanisms underlying maintenance DNA methylation.　Using Xenopus egg extracts, we successfully reproduced maintenance DNA methylation in vitro. Dnmt1 depletion resulted in a dramatic accumulation of Uhrf1-dependent ubiquitylation of histone H3 at lysine 23. Dnmt1 preferentially associated with ubiquitylated H3 in vitro. In mammalian cells, we also found Uhrf1-dependent uqibuityltion of H3 specifically during S phase. The RING finger mutant of Uhrf1 failed to recruit Dnmt1 to DNA replication sites and maintain DNA methylation in mammalian cultured cells.
2. Molecular mechanisms underlying senescence induction. Normal human diploid fibroblasts (HDFs) exposed to various senescence-inducing stimuli undergo a mitosis skip before entry into permanent cell cycle arrest. This mitosis skip is mediated by both p53-dependent premature activation of APC/CCdh1 and pRb family protein-dependent transcriptional suppression of mitotic regulators.

Free Research Field

分子細胞生物学