The role of CpG dinucleotides to generate PcG-repressive genomic domains

2015 Fiscal Year Final Research Report

• Project/Area Number: 23249015
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: KOSEKI HARUHIKO 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, グループディレクター (40225446)
• Project Period (FY): 2011-04-01 – 2016-03-31
• Keywords: ポリコム群 / CpG配列 / クロマチン / エピジェネティクス / マウス

Outline of Final Research Achievements

Here, we reveal that protracted binding of NP95 to hemimethylated sites has an unexpected role for disrupting transcriptional silencing of CpG-rich proviral sequences in the mouse genome. Exploiting conditional deletions of Dnmt1 and Np95, we show that in Dnmt1-ablated cells undergoing passive demethylation, NP95 is required for activation of endogenous retrotransposons (ERVs), while, in Np95-ablated cells, the same ERVs remain silenced, despite acute demethylation. Furthermore, we demonstrate that in the absence of NP95, the H3K9 methyltransferase SETDB1 maintains ERV silencing, while in the absence of DNMT1, prolonged binding of NP95 to hemimethylated DNA disrupts SETDB1-dependent deposition of H3K9me3. Taken together, our observations reveal that the fidelity of histone methylation-dependent proviral silencing is dependent upon timely maintenance DNA methylation.

Free Research Field

エピジェネティクス