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 Li; Frederic A. Bard; Yuin Han Loh

doi:10.1016/j.cell.2015.08.037

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

Pharmacology

Research output: Contribution to journal › Article › peer-review

85 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 language	English (US)
Pages (from-to)	230-245
Number of pages	16
Journal	Cell
Volume	163
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2015.08.037
State	Published - Sep 24 2015

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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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

Yang, BX, El Farran, CA, Guo, HC, Yu, T, Fang, HT, Wang, HF, Schlesinger, S, Seah, YFS, Goh, GYL, Neo, SP, Li, Y, Lorincz, MC, Tergaonkar, V, Lim, TM, Chen, L, Gunaratne, J, Collins, JJ, Goff, SP, Daley, GQ, Li, H, Bard, FA & Loh, YH 2015, 'Systematic Identification of Factors for Provirus Silencing in Embryonic Stem Cells', Cell, vol. 163, no. 1, pp. 230-245. https://doi.org/10.1016/j.cell.2015.08.037

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title = "Systematic Identification of Factors for Provirus Silencing in Embryonic Stem Cells",

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.",

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

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doi = "10.1016/j.cell.2015.08.037",

language = "English (US)",

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T1 - Systematic Identification of Factors for Provirus Silencing in Embryonic Stem Cells

AU - Yang, Bin Xia

AU - El Farran, Chadi A.

AU - Guo, Hong Chao

AU - Yu, Tao

AU - Fang, Hai Tong

AU - Wang, Hao Fei

AU - Schlesinger, Sharon

AU - Seah, Yu Fen Samantha

AU - Goh, Germaine Yen Lin

AU - Neo, Suat Peng

AU - Li, Yinghui

AU - Lorincz, Matthew C.

AU - Tergaonkar, Vinay

AU - Lim, Tit Meng

AU - Chen, Lingyi

AU - Gunaratne, Jayantha

AU - Collins, James J.

AU - Goff, Stephen P.

AU - Daley, George Q.

AU - Li, Hu

AU - Bard, Frederic A.

AU - Loh, Yuin Han

PY - 2015/9/24

Y1 - 2015/9/24

N2 - 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.

AB - 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.

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JF - Cell

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Systematic Identification of Factors for Provirus Silencing in Embryonic Stem Cells

Abstract

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