Systematic Identification of Factors for Provirus Silencing in Embryonic Stem Cells

被引：159

作者：

Yang, Bin Xia ^{[1
]}

El Farran, Chadi A. ^{[1
,2
]}

Guo, Hong Chao ^{[3
]}

Yu, Tao ^{[1
,2
]}

Fang, Hai Tong ^{[1
]}

Wang, Hao Fei ^{[1
,2
]}

Schlesinger, Sharon ^{[4
,5
]}

Seah, Yu Fen Samantha ^{[1
]}

Goh, Germaine Yen Lin ^{[6
]}

Neo, Suat Peng ^{[7
]}

Li, Yinghui ^{[9
]}

Lorincz, Matthew C. ^{[10
]}

Tergaonkar, Vinay ^{[9
,22
]}

Lim, Tit-Meng ^{[2
]}

Chen, Lingyi ^{[3
]}

Gunaratne, Jayantha ^{[7
,8
]}

Collins, James J. ^{[11
,12
,13
,14
]}

Goff, Stephen P. ^{[4
,5
,15
]}

Daley, George Q. ^{[14
,16
,17
,18
,19
,20
]}

Li, Hu ^{[21
]}

Bard, Frederic A. ^{[6
,22
]}

Loh, Yuin-Han ^{[1
,2
]}

机构：

[1] A STAR Inst Mol & Cell Biol, Epigenet & Cell Fates Lab, Singapore 138673, Singapore

[2] Natl Univ Singapore, Dept Biol Sci, Singapore 117543, Singapore

[3] Nankai Univ, Coll Life Sci, Tianjin 300071, Peoples R China

[4] Columbia Univ, Dept Biochem & Mol Biophys, New York, NY 10032 USA

[5] Columbia Univ, Dept Microbiol & Immunol, New York, NY 10032 USA

[6] A STAR Inst Mol & Cell Biol, Membrane Traff Lab, Singapore 138673, Singapore

[7] A STAR Inst Mol & Cell Biol, Quantitat Prote Grp, Singapore 138673, Singapore

[8] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Anat, Singapore 117597, Singapore

[9] A STAR Inst Mol & Cell Biol, Lab NF KB Signaling, Div Canc Genet & Therapeut, Singapore 138673, Singapore

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

[11] MIT, Inst Med Engn & Sci, Dept Biol Engn, Synthet Biol Ctr, Cambridge, MA 02139 USA

[12] Broad Inst MIT & Harvard, Cambridge, MA 02139 USA

[13] Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA

[14] Howard Hughes Med Inst, Boston, MA 02115 USA

[15] Howard Hughes Med Inst, New York, NY 10032 USA

[16] Boston Childrens Hosp, Div Pediat Hematol Oncol, Stem Cell Transplantat Program, Boston, MA 02115 USA

[17] Dana Farber Canc Inst, Boston, MA 02115 USA

[18] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

[19] Harvard Stem Cell Inst, Boston, MA 02115 USA

[20] Manton Ctr Orphan Dis Res, Boston, MA 02115 USA

[21] Mayo Clin, Dept Mol Pharmacol & Expt Therapeut, Ctr Individualized Med, Rochester, MN 55905 USA

[22] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, Singapore 119077, Singapore

来源：

CELL | 2015年 / 163卷 / 01期

关键词：

PRIMER-BINDING SITE; MURINE LEUKEMIA-VIRUS; LONG TERMINAL REPEAT; ENDOGENOUS RETROVIRUSES; DEPENDENT RESTRICTION; DNA-REPLICATION; HISTONE H3.3; HP1; METHYLATION; EXPRESSION;

D O I：

10.1016/j.cell.2015.08.037

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Embryonic stem cells (ESCs) repress the expression of exogenous proviruses and endogenous retroviruses (ERVs). Here, we systematically dissected the cellular factors involved in provirus repression in embryonic carcinomas (ECs) and ESCs by a genome-wide siRNA screen. Histone chaperones (Chaf1a/b), sumoylation factors (Sumo2/Ube2i/Sae1/Uba2/Senp6), and chromatin modifiers (Trim28/Eset/At-f7ip) are key determinants that establish provirus silencing. RNA-seq analysis uncovered the roles of Chaf1a/b and sumoylation modifiers in the repression of ERVs. ChIP-seq analysis demonstrates direct recruitment of Chaf1a and Sumo2 to ERVs. Chaf1a reinforces transcriptional repression via its interaction with members of the NuRD complex (Kdm1a, Hdac1/2) and Eset, while Sumo2 orchestrates the provirus repressive function of the canonical Zfp809/Trim28/Eset machinery by sumoylation of Trim28. Our study reports a genome-wide atlas of functional nodes that mediate proviral silencing in ESCs and illuminates the comprehensive, interconnected, and multi-layered genetic and epigenetic mechanisms by which ESCs repress retroviruses within the genome.

引用

页码：230 / 245

页数：16

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