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Cell. 2015 Sep 24;163(1):230-45. doi: 10.1016/j.cell.2015.08.037. Epub 2015 Sep 10.

Systematic identification of factors for provirus silencing in embryonic stem cells.

Author information

1
Epigenetics and Cell Fates Laboratory, A(∗)STAR Institute of Molecular and Cell Biology, 61 Biopolis Drive Proteos, Singapore 138673, Singapore.
2
Epigenetics and Cell Fates Laboratory, A(∗)STAR Institute of Molecular and Cell Biology, 61 Biopolis Drive Proteos, Singapore 138673, Singapore; Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore.
3
College of Life Sciences, Nankai University, Tianjin 300071, China.
4
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Department of Microbiology and Immunology, Columbia University, New York, NY 10032, USA.
5
Membrane Traffic Laboratory, A(∗)STAR Institute of Molecular and Cell Biology, 61 Biopolis Drive Proteos, Singapore 138673, Singapore.
6
Quantitative Proteomics Group, A(∗)STAR Institute of Molecular and Cell Biology, 61 Biopolis Drive Proteos, Singapore 138673, Singapore.
7
Division of Cancer Genetics and Therapeutics, Laboratory of NF-κB Signaling, A(∗)STAR Institute of Molecular and Cell Biology, 61 Biopolis Drive Proteos, Singapore 138673, Singapore.
8
Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
9
Division of Cancer Genetics and Therapeutics, Laboratory of NF-κB Signaling, A(∗)STAR Institute of Molecular and Cell Biology, 61 Biopolis Drive Proteos, Singapore 138673, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore.
10
Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore.
11
Quantitative Proteomics Group, A(∗)STAR Institute of Molecular and Cell Biology, 61 Biopolis Drive Proteos, Singapore 138673, Singapore; Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
12
Department of Biological Engineering, Synthetic Biology Center, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston, MA 02115, USA.
13
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Department of Microbiology and Immunology, Columbia University, New York, NY 10032, USA; Howard Hughes Medical Institute, New York, NY 10032, USA.
14
Howard Hughes Medical Institute, Boston, MA 02115, USA; Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Boston, MA 02115, USA; Manton Center for Orphan Disease Research, Boston, MA 02115, USA.
15
Center for Individualized Medicine, Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
16
Membrane Traffic Laboratory, A(∗)STAR Institute of Molecular and Cell Biology, 61 Biopolis Drive Proteos, Singapore 138673, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore.
17
Epigenetics and Cell Fates Laboratory, A(∗)STAR Institute of Molecular and Cell Biology, 61 Biopolis Drive Proteos, Singapore 138673, Singapore; Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore. Electronic address: yhloh@imcb.a-star.edu.sg.

Abstract

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/Atf7ip) 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.

PMID:
26365490
PMCID:
PMC4686136
DOI:
10.1016/j.cell.2015.08.037
[Indexed for MEDLINE]
Free PMC Article

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