Systematic Identification of Factors for Provirus Silencing in Embryonic Stem Cells

Bin Xia Yang, Chadi A. El Farran, Hong Chao Guo, Tao Yu, Hai Tong Fang, Hao Fei Wang, Sharon Schlesinger, Yu Fen Samantha Seah, Germaine Yen Lin Goh, Suat Peng Neo, Yinghui Li, Matthew C. Lorincz, Vinay Tergaonkar, Tit Meng Lim, Lingyi Chen, Jayantha Gunaratne, James J. Collins, Stephen P. Goff, George Q. Daley, Hu LiFrederic A. Bard, Yuin Han Loh

Research output: Contribution to journalArticle

70 Scopus citations

Abstract

Summary 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.

Original languageEnglish (US)
Pages (from-to)230-245
Number of pages16
JournalCell
Volume163
Issue number1
DOIs
StatePublished - Sep 24 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Yang, B. X., El Farran, C. A., Guo, H. C., Yu, T., Fang, H. T., Wang, H. F., Schlesinger, S., Seah, Y. F. S., Goh, G. Y. L., Neo, S. P., Li, Y., Lorincz, M. C., Tergaonkar, V., Lim, T. M., Chen, L., Gunaratne, J., Collins, J. J., Goff, S. P., Daley, G. Q., ... Loh, Y. H. (2015). Systematic Identification of Factors for Provirus Silencing in Embryonic Stem Cells. Cell, 163(1), 230-245. https://doi.org/10.1016/j.cell.2015.08.037