Mechanistic link between DNA methylation and H3K9 trimethylation in mammalian cells mediated by two novel SRA proteins- Np95 and Np97

2015 Fiscal Year Final Research Report

• Project/Area Number: 26870847
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: System genome science; Genome biology
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: SHARIF JAFAR 国立研究開発法人理化学研究所, 統合生命医科学研究センター, 研究員 (00577968)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Keywords: NP95 / Hemimethylated DNA / SETDB1 / H3K9me3 / Endogenous retroviruses / IAP / Placenta / Development

Outline of Final Research Achievements

In the present project, I investigated the role of the mammalian SRA proteins NP95 and NP97 for regulation of H3K9me3, a repressive epigenetic mark, in mammalian cells. I found that protracted binding of NP95 to hemimethylated DNA sites (cytosine methylation in only one strand of the CpG dyad) leads to transient disruption of H3K9me3-dependent transcriptional silencing. I showed that NP95 binding to naturally occurring hemimethylated sites in the placenta gives rise to dramatic activation of a specific class of CpG-rich endogenous retroviruses (LTR containing DNA sequences) via disruption of H3K9me3 mediated silencing. This pathway is inactive in the embryo proper due to the high fidelity of the NP95-DNMT1 mediated maintenance methylation pathway (Sharif et al, Nature, 2007), which prevent accumulation of hemimethylated DNA. I recently reported these observations in a scientific paper (Sharif et al., Cell Stem cell, 2016).

Free Research Field

Epigenetics; Transcription; Tetrotransposons