RNA-dependent chromatin targeting of TET2 for endogenous retrovirus control in pluripotent stem cells

Diana Guallar; Xianju Bi; Jose Angel Pardavila; Xin Huang; Carmen Saenz; Xianle Shi; Hongwei Zhou; Francesco Faiola; Junjun Ding; Phensinee Haruehanroengra; Fan Yang; Dan Li; Carlos Sanchez-Priego; Arven Saunders; Feng Pan; Victor Julian Valdes; Kevin Kelley; Miguel G. Blanco; Lingyi Chen; Huayan Wang; Jia Sheng; Mingjiang Xu; Miguel Fidalgo; Xiaohua Shen; Jianlong Wang

doi:10.1038/s41588-018-0060-9

RNA-dependent chromatin targeting of TET2 for endogenous retrovirus control in pluripotent stem cells

Diana Guallar, Xianju Bi, Jose Angel Pardavila, Xin Huang, Carmen Saenz, Xianle Shi, Hongwei Zhou, Francesco Faiola, Junjun Ding, Phensinee Haruehanroengra, Fan Yang, Dan Li, Carlos Sanchez-Priego, Arven Saunders, Feng Pan, Victor Julian Valdes, Kevin Kelley, Miguel G. Blanco, Lingyi Chen, Huayan WangJia Sheng, Mingjiang Xu, Miguel Fidalgo, Xiaohua Shen, Jianlong Wang

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

82 Scopus citations

Abstract

Ten-eleven translocation (TET) proteins play key roles in the regulation of DNA-methylation status by oxidizing 5-methylcytosine (5mC) to generate 5-hydroxymethylcytosine (5hmC), which can both serve as a stable epigenetic mark and participate in active demethylation. Unlike the other members of the TET family, TET2 does not contain a DNA-binding domain, and it remains unclear how it is recruited to chromatin. Here we show that TET2 is recruited by the RNA-binding protein Paraspeckle component 1 (PSPC1) through transcriptionally active loci, including endogenous retroviruses (ERVs) whose long terminal repeats (LTRs) have been co-opted by mammalian genomes as stage- and tissue-specific transcriptional regulatory modules. We found that PSPC1 and TET2 contribute to ERVL and ERVL-associated gene regulation by both transcriptional repression via histone deacetylases and post-transcriptional destabilization of RNAs through 5hmC modification. Our findings provide evidence for a functional role of transcriptionally active ERVs as specific docking sites for RNA epigenetic modulation and gene regulation.

Original language	English
Pages (from-to)	443-451
Number of pages	9
Journal	Nature Genetics
Volume	50
Issue number	3
DOIs	https://doi.org/10.1038/s41588-018-0060-9
State	Published - 1 Mar 2018

Access to Document

10.1038/s41588-018-0060-9

Cite this

Guallar, D., Bi, X., Pardavila, J. A., Huang, X., Saenz, C., Shi, X., Zhou, H., Faiola, F., Ding, J., Haruehanroengra, P., Yang, F., Li, D., Sanchez-Priego, C., Saunders, A., Pan, F., Valdes, V. J., Kelley, K., Blanco, M. G., Chen, L., ... Wang, J. (2018). RNA-dependent chromatin targeting of TET2 for endogenous retrovirus control in pluripotent stem cells. Nature Genetics, 50(3), 443-451. https://doi.org/10.1038/s41588-018-0060-9

@article{38ace330519c4218b68987216f0b3ab8,

title = "RNA-dependent chromatin targeting of TET2 for endogenous retrovirus control in pluripotent stem cells",

abstract = "Ten-eleven translocation (TET) proteins play key roles in the regulation of DNA-methylation status by oxidizing 5-methylcytosine (5mC) to generate 5-hydroxymethylcytosine (5hmC), which can both serve as a stable epigenetic mark and participate in active demethylation. Unlike the other members of the TET family, TET2 does not contain a DNA-binding domain, and it remains unclear how it is recruited to chromatin. Here we show that TET2 is recruited by the RNA-binding protein Paraspeckle component 1 (PSPC1) through transcriptionally active loci, including endogenous retroviruses (ERVs) whose long terminal repeats (LTRs) have been co-opted by mammalian genomes as stage- and tissue-specific transcriptional regulatory modules. We found that PSPC1 and TET2 contribute to ERVL and ERVL-associated gene regulation by both transcriptional repression via histone deacetylases and post-transcriptional destabilization of RNAs through 5hmC modification. Our findings provide evidence for a functional role of transcriptionally active ERVs as specific docking sites for RNA epigenetic modulation and gene regulation.",

author = "Diana Guallar and Xianju Bi and Pardavila, {Jose Angel} and Xin Huang and Carmen Saenz and Xianle Shi and Hongwei Zhou and Francesco Faiola and Junjun Ding and Phensinee Haruehanroengra and Fan Yang and Dan Li and Carlos Sanchez-Priego and Arven Saunders and Feng Pan and Valdes, {Victor Julian} and Kevin Kelley and Blanco, {Miguel G.} and Lingyi Chen and Huayan Wang and Jia Sheng and Mingjiang Xu and Miguel Fidalgo and Xiaohua Shen and Jianlong Wang",

note = "Funding Information: National Natural Science Foundation of China (31471219 and 31428010) and the Center for Life Sciences (CLS) at Tsinghua University. Additional support was provided by the Agencia Estatal de Investigaci{\'o}n (BFU2016-80899-P to M.F.) (AEI/FEDER, UE) and the Conseller{\'i}a de Cultura, Educaci{\'o}n e Ordenaci{\'o}n Universitaria (ED431F 2016/016 to M.F.). Funding Information: We thank Y. Kurihara for PSPC1 constructs, T. Macfarlan for the Zfp352-luciferase reporter construct, R. Jaenisch for the Tet-TKO ESC line, D. Trono for the Trim28-cKO line, and D.M. Gilbert and Y. Shinkai for the Ehmt2-cKO line. We also thank the medical illustrator J. Gregory from Icahn School of Medicine at Mount Sinai for the model drawing. This research was funded by the US National Institutes of Health (NIH) (grants 1R01-GM095942 and R21HD087722 to J.W.; grant R01HL112294 to M.X.) and the Empire State Stem Cell Fund through the New York State Department of Health (NYSTEM) (grants C028103 and C028121 to J.W.). J.W. is a recipient of an Irma T. Hirschl and Weill-Caulier Trusts Career Scientist Award, and M.F. is a recipient of a Ram{\'o}n y Cajal contract (RYC-2014-16779) from the Ministerio de Econom{\'i}a y Competitividad of Spain. The research from the Shen laboratory is supported by the Funding Information: We thank Y. Kurihara for PSPC1 constructs, T. Macfarlan for the Zfp352-luciferase reporter construct, R. Jaenisch for the Tet-TKO ESC line, D. Trono for the Trim28- cKO line, and D.M. Gilbert and Y. Shinkai for the Ehmt2-cKO line. We also thank the medical illustrator J. Gregory from Icahn School of Medicine at Mount Sinai for the model drawing. This research was funded by the US National Institutes of Health (NIH) (grants 1R01-GM095942 and R21HD087722 to J.W.; grant R01HL112294 to M.X.) and the Empire State Stem Cell Fund through the New York State Department of Health (NYSTEM) (grants C028103 and C028121 to J.W.). J.W. is a recipient of an Irma T. Hirschl and Weill-Caulier Trusts Career Scientist Award, and M.F. is a recipient of a Ram?n y Cajal contract (RYC-2014-16779) from the Ministerio de Econom?a y Competitividad of Spain. The research from the Shen laboratory is supported by the National Natural Science Foundation of China (31471219 and 31428010) and the Center for Life Sciences (CLS) at Tsinghua University. Additional support was provided by the Agencia Estatal de Investigaci?n (BFU2016-80899-P to M.F.) (AEI/FEDER, UE) and the Conseller?a de Cultura, Educaci?n e Ordenacin Universitaria (ED431F 2016/016 to M.F.). Publisher Copyright: {\textcopyright} 2018 The Author(s).",

year = "2018",

month = mar,

day = "1",

doi = "10.1038/s41588-018-0060-9",

language = "English",

volume = "50",

pages = "443--451",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "3",

}

Guallar, D, Bi, X, Pardavila, JA, Huang, X, Saenz, C, Shi, X, Zhou, H, Faiola, F, Ding, J, Haruehanroengra, P, Yang, F, Li, D, Sanchez-Priego, C, Saunders, A, Pan, F, Valdes, VJ, Kelley, K, Blanco, MG, Chen, L, Wang, H, Sheng, J, Xu, M, Fidalgo, M, Shen, X & Wang, J 2018, 'RNA-dependent chromatin targeting of TET2 for endogenous retrovirus control in pluripotent stem cells', Nature Genetics, vol. 50, no. 3, pp. 443-451. https://doi.org/10.1038/s41588-018-0060-9

TY - JOUR

T1 - RNA-dependent chromatin targeting of TET2 for endogenous retrovirus control in pluripotent stem cells

AU - Guallar, Diana

AU - Bi, Xianju

AU - Pardavila, Jose Angel

AU - Huang, Xin

AU - Saenz, Carmen

AU - Shi, Xianle

AU - Zhou, Hongwei

AU - Faiola, Francesco

AU - Ding, Junjun

AU - Haruehanroengra, Phensinee

AU - Yang, Fan

AU - Li, Dan

AU - Sanchez-Priego, Carlos

AU - Saunders, Arven

AU - Pan, Feng

AU - Valdes, Victor Julian

AU - Kelley, Kevin

AU - Blanco, Miguel G.

AU - Chen, Lingyi

AU - Wang, Huayan

AU - Sheng, Jia

AU - Xu, Mingjiang

AU - Fidalgo, Miguel

AU - Shen, Xiaohua

AU - Wang, Jianlong

N1 - Funding Information: National Natural Science Foundation of China (31471219 and 31428010) and the Center for Life Sciences (CLS) at Tsinghua University. Additional support was provided by the Agencia Estatal de Investigación (BFU2016-80899-P to M.F.) (AEI/FEDER, UE) and the Consellería de Cultura, Educación e Ordenación Universitaria (ED431F 2016/016 to M.F.). Funding Information: We thank Y. Kurihara for PSPC1 constructs, T. Macfarlan for the Zfp352-luciferase reporter construct, R. Jaenisch for the Tet-TKO ESC line, D. Trono for the Trim28-cKO line, and D.M. Gilbert and Y. Shinkai for the Ehmt2-cKO line. We also thank the medical illustrator J. Gregory from Icahn School of Medicine at Mount Sinai for the model drawing. This research was funded by the US National Institutes of Health (NIH) (grants 1R01-GM095942 and R21HD087722 to J.W.; grant R01HL112294 to M.X.) and the Empire State Stem Cell Fund through the New York State Department of Health (NYSTEM) (grants C028103 and C028121 to J.W.). J.W. is a recipient of an Irma T. Hirschl and Weill-Caulier Trusts Career Scientist Award, and M.F. is a recipient of a Ramón y Cajal contract (RYC-2014-16779) from the Ministerio de Economía y Competitividad of Spain. The research from the Shen laboratory is supported by the Funding Information: We thank Y. Kurihara for PSPC1 constructs, T. Macfarlan for the Zfp352-luciferase reporter construct, R. Jaenisch for the Tet-TKO ESC line, D. Trono for the Trim28- cKO line, and D.M. Gilbert and Y. Shinkai for the Ehmt2-cKO line. We also thank the medical illustrator J. Gregory from Icahn School of Medicine at Mount Sinai for the model drawing. This research was funded by the US National Institutes of Health (NIH) (grants 1R01-GM095942 and R21HD087722 to J.W.; grant R01HL112294 to M.X.) and the Empire State Stem Cell Fund through the New York State Department of Health (NYSTEM) (grants C028103 and C028121 to J.W.). J.W. is a recipient of an Irma T. Hirschl and Weill-Caulier Trusts Career Scientist Award, and M.F. is a recipient of a Ram?n y Cajal contract (RYC-2014-16779) from the Ministerio de Econom?a y Competitividad of Spain. The research from the Shen laboratory is supported by the National Natural Science Foundation of China (31471219 and 31428010) and the Center for Life Sciences (CLS) at Tsinghua University. Additional support was provided by the Agencia Estatal de Investigaci?n (BFU2016-80899-P to M.F.) (AEI/FEDER, UE) and the Conseller?a de Cultura, Educaci?n e Ordenacin Universitaria (ED431F 2016/016 to M.F.). Publisher Copyright: © 2018 The Author(s).

PY - 2018/3/1

Y1 - 2018/3/1

N2 - Ten-eleven translocation (TET) proteins play key roles in the regulation of DNA-methylation status by oxidizing 5-methylcytosine (5mC) to generate 5-hydroxymethylcytosine (5hmC), which can both serve as a stable epigenetic mark and participate in active demethylation. Unlike the other members of the TET family, TET2 does not contain a DNA-binding domain, and it remains unclear how it is recruited to chromatin. Here we show that TET2 is recruited by the RNA-binding protein Paraspeckle component 1 (PSPC1) through transcriptionally active loci, including endogenous retroviruses (ERVs) whose long terminal repeats (LTRs) have been co-opted by mammalian genomes as stage- and tissue-specific transcriptional regulatory modules. We found that PSPC1 and TET2 contribute to ERVL and ERVL-associated gene regulation by both transcriptional repression via histone deacetylases and post-transcriptional destabilization of RNAs through 5hmC modification. Our findings provide evidence for a functional role of transcriptionally active ERVs as specific docking sites for RNA epigenetic modulation and gene regulation.

AB - Ten-eleven translocation (TET) proteins play key roles in the regulation of DNA-methylation status by oxidizing 5-methylcytosine (5mC) to generate 5-hydroxymethylcytosine (5hmC), which can both serve as a stable epigenetic mark and participate in active demethylation. Unlike the other members of the TET family, TET2 does not contain a DNA-binding domain, and it remains unclear how it is recruited to chromatin. Here we show that TET2 is recruited by the RNA-binding protein Paraspeckle component 1 (PSPC1) through transcriptionally active loci, including endogenous retroviruses (ERVs) whose long terminal repeats (LTRs) have been co-opted by mammalian genomes as stage- and tissue-specific transcriptional regulatory modules. We found that PSPC1 and TET2 contribute to ERVL and ERVL-associated gene regulation by both transcriptional repression via histone deacetylases and post-transcriptional destabilization of RNAs through 5hmC modification. Our findings provide evidence for a functional role of transcriptionally active ERVs as specific docking sites for RNA epigenetic modulation and gene regulation.

UR - http://www.scopus.com/inward/record.url?scp=85042534855&partnerID=8YFLogxK

U2 - 10.1038/s41588-018-0060-9

DO - 10.1038/s41588-018-0060-9

M3 - Article

C2 - 29483655

AN - SCOPUS:85042534855

SN - 1061-4036

VL - 50

SP - 443

EP - 451

JO - Nature Genetics

JF - Nature Genetics

IS - 3

ER -

RNA-dependent chromatin targeting of TET2 for endogenous retrovirus control in pluripotent stem cells

Abstract

Access to Document

Fingerprint

Cite this