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

2015 Fiscal Year Annual Research Report

• Project/Area Number: 26870847
• 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 / SETDB1 / H3K9me3 / hemi-methylated DNA / LTR-derived sequences

Outline of Annual Research Achievements

On the basis of the young scientist (B) research project, recently I have reported a role for the SRA protein NP95 to recognize ectopic hemi-methylated DNA, induced by acute depletion of DNMT1, for aberrant activation of specific LTR-derived sequences in the genome (Sharif et al., Cell Stem Cell, 2016). I have previously shown that hemi-methylated DNA recognition by NP95 is essential for maintenance of DNA methylation in mammals (Sharif et al., Nature, 2007). Therefore, in the recent paper I extend this previous finding by showing that the association of NP95 to hemi-methylated DNA could lead to a sequence of epigenetic events, notably, disruption of SETDB1-mediated H3K9me3 pathway that represses LTR-derived sequences. I have also shown that such NP95 and hemi-methylated DNA interactions could play a role to induce robust transcription of LTR-derived sequences in the placenta. LTR-derived sequences were thought to be silenced in most, if not all, cell types; and my research shows that this is not the case. Instead, an interplay between NP95, hemi-methylated DNA and SETDB1 ensures silencing of LTR-derived sequences in the embryo proper, but paradoxically allows the transcription of such parasitic sequences in the extra-embryonic tissues (e.g placenta).

Research Products

• [Int'l Joint Research] University of British Columbia(Canada)
  • Country Name: Canada
  • Counterpart Institution: University of British Columbia
• [Int'l Joint Research] Virginia Tech(米国)
  • Country Name: U.S.A.
  • Counterpart Institution: Virginia Tech
• [Journal Article] Activation of Endogenous Retroviruses in Dnmt1-/- ESCs Involves Disruption of SETDB1-Mediated Repression by NP95 Binding to Hemimethylated DNA. (2016)
  • Author(s): Sharif J, Endo TA, Nakayama M, Karimi MM, Shimada M, Katsuyama K, Goyal P, Brind'Amour J, Sun MA, Sun Z, Ishikura T, Mizutani-Koseki Y, Ohara O, Shinkai Y, Nakanishi M, Xie H, Lorincz MC, Koseki H.
  • Journal Title: Cell Stem Cell Volume: Epub ahead of print Pages: 999
  • DOI: 10.1016/j.stem.2016.03.013
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant