Activation of Endogenous Retroviruses in Dnmt1-/- ESCs Involves Disruption of SETDB1-Mediated Repression by NP95 Binding to Hemimethylated DNA

被引：65

作者：

Sharif, Jafar ^{[1
]}

Endo, Takaho A. ^{[2
]}

Nakayama, Manabu ^{[3
]}

Karimi, Mohammad M. ^{[4
]}

Shimada, Midori ^{[5
]}

Katsuyama, Kayoko ^{[1
]}

Goyal, Preeti ^{[4
]}

Brind'Amour, Julie ^{[4
]}

Sun, Ming-An ^{[6
]}

Sun, Zhixiong ^{[6
,7
]}

Ishikura, Tomoyuki ^{[1
]}

Mizutani-Koseki, Yoko ^{[1
]}

Ohara, Osamu ^{[2
,3
]}

Shinkai, Yoichi ^{[8
]}

Nakanishi, Makoto ^{[5
]}

Xie, Hehuang ^{[6
,7
]}

Lorincz, Matthew C. ^{[4
]}

Koseki, Haruhiko ^{[1
]}

机构：

[1] RIKEN Ctr Integrat Med Sci IMS, Lab Dev Genet, Tsurumi Ku, 1-7-22 Suehiro Cho, Yokohama, Kanagawa 2300045, Japan

[2] RIKEN Ctr Integrat Med Sci IMS, Lab Integrat Genom, Tsurumi Ku, 1-7-22 Suehiro Cho, Yokohama, Kanagawa 2300045, Japan

[3] Kazusa DNA Res Inst, Dept Technol Dev, 2-6-7 Kazusa Kamatari, Kisarazu, Chiba 2920818, Japan

[4] Univ British Columbia, Dept Med Genet, Inst Life Sci, Vancouver, BC V6T 1Z3, Canada

[5] Nagoya City Univ, Grad Sch Med Sci, Dept Cell Biol, Mizuho Ku, 1 Kawasumi,Mizuho Cho, Nagoya, Aichi 4678601, Japan

[6] Virginia Tech, Virginia Bioinformat Inst, Blacksburg, VA 24060 USA

[7] Virginia Tech, Dept Biol Sci, Blacksburg, VA 24060 USA

[8] RIKEN, Cellular Memory Lab, 2-1 Hirosawa, Wako, Saitama 3510198, Japan

来源：

CELL STEM CELL | 2016年 / 19卷 / 01期

基金：

加拿大健康研究院;

关键词：

EMBRYONIC STEM-CELLS; PRIMORDIAL GERM-CELLS; CYTOSINE METHYLATION; UHRF1; DEMETHYLATION; MAINTENANCE; DYNAMICS; ELEMENTS; GENES; MICE;

D O I：

10.1016/j.stem.2016.03.013

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

Repression of endogenous retroviruses (ERVs) in mammals involves several epigenetic mechanisms. Acute loss of the maintenance methyltransferase Dnmt1 induces widespread DNA demethylation and transcriptional activation of ERVs, including CpG-rich IAP (intracisternal A particle) proviruses. Here, we show that this effect is not due simply to a loss of DNA methylation. Conditional deletions reveal that both Dnmt1 and Np95 are essential for maintenance DNA methylation. However, while IAPs are derepressed in Dnmt1-ablated embryos and embryonic stem cells (ESCs), these ERVs remain silenced when Np95 is deleted alone or in combination with Dnmt1. This paradoxical phenotype results from an ectopic interaction between NP95 and the H3K9 methyltransferase SETDB1. Normally, SETDB1 maintains silencing of IAPs, but in the absence of DNMT1, prolonged binding of NP95 to hemimethylated DNA transiently disrupts SETDB1-dependent H3K9me3 deposition. Thus, our observations reveal an unexpected antagonistic interplay between two repressive pathways involved in retroviral silencing in mammalian cells.

引用

页码：81 / 94

页数：14

共 35 条

[1] Selective impairment of methylation maintenance is the major cause of DNA methylation reprogramming in the early embryo [J].