G-tract RNA Removes Polycomb Repressive Complex 2 from Genes

Overview

Journal Nat Struct Mol Biol

Specialties Cell Biology
Molecular Biology

Date 2019 Sep 25

PMID 31548724

Citations 58

Authors

Manuel Beltran

Manuel Tavares

Neil Justin

Garima Khandelwal

John Ambrose

Benjamin M Foster

Kaylee B Worlock

Andrey Tvardovskiy

Simone Kunzelmann

Javier Herrero

Till Bartke

Steven J Gamblin

Jon R Wilson

Richard G Jenner

Affiliations

Soon will be listed here.

Abstract

Polycomb repressive complex 2 (PRC2) maintains repression of cell-type-specific genes but also associates with genes ectopically in cancer. While it is currently unknown how PRC2 is removed from genes, such knowledge would be useful for the targeted reversal of deleterious PRC2 recruitment events. Here, we show that G-tract RNA specifically removes PRC2 from genes in human and mouse cells. PRC2 preferentially binds G tracts within nascent precursor mRNA (pre-mRNA), especially within predicted G-quadruplex structures. G-quadruplex RNA evicts the PRC2 catalytic core from the substrate nucleosome. In cells, PRC2 transfers from chromatin to pre-mRNA upon gene activation, and chromatin-associated G-tract RNA removes PRC2, leading to H3K27me3 depletion from genes. Targeting G-tract RNA to the tumor suppressor gene CDKN2A in malignant rhabdoid tumor cells reactivates the gene and induces senescence. These data support a model in which pre-mRNA evicts PRC2 during gene activation and provides the means to selectively remove PRC2 from specific genes.

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References

Skalska L, Beltran-Nebot M, Ule J, Jenner R . Regulatory feedback from nascent RNA to chromatin and transcription. Nat Rev Mol Cell Biol. 2017; 18(5):331-337. DOI: 10.1038/nrm.2017.12. View

Holoch D, Margueron R . Mechanisms Regulating PRC2 Recruitment and Enzymatic Activity. Trends Biochem Sci. 2017; 42(7):531-542. DOI: 10.1016/j.tibs.2017.04.003. View

Schuettengruber B, Bourbon H, Di Croce L, Cavalli G . Genome Regulation by Polycomb and Trithorax: 70 Years and Counting. Cell. 2017; 171(1):34-57. DOI: 10.1016/j.cell.2017.08.002. View

Comet I, Riising E, LeBlanc B, Helin K . Maintaining cell identity: PRC2-mediated regulation of transcription and cancer. Nat Rev Cancer. 2016; 16(12):803-810. DOI: 10.1038/nrc.2016.83. View

Qi W, Chan H, Teng L, Li L, Chuai S, Zhang R . Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation. Proc Natl Acad Sci U S A. 2012; 109(52):21360-5. PMC: 3535655. DOI: 10.1073/pnas.1210371110. View

Knutson S, Warholic N, Wigle T, Klaus C, Allain C, Raimondi A . Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. Proc Natl Acad Sci U S A. 2013; 110(19):7922-7. PMC: 3651445. DOI: 10.1073/pnas.1303800110. View

Caganova M, Carrisi C, Varano G, Mainoldi F, Zanardi F, Germain P . Germinal center dysregulation by histone methyltransferase EZH2 promotes lymphomagenesis. J Clin Invest. 2013; 123(12):5009-22. PMC: 3859423. DOI: 10.1172/JCI70626. View

Beguelin W, Popovic R, Teater M, Jiang Y, Bunting K, Rosen M . EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell. 2013; 23(5):677-92. PMC: 3681809. DOI: 10.1016/j.ccr.2013.04.011. View

McCabe M, Ott H, Ganji G, Korenchuk S, Thompson C, Van Aller G . EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature. 2012; 492(7427):108-12. DOI: 10.1038/nature11606. View

10.

Mohammad F, Weissmann S, LeBlanc B, Pandey D, Hojfeldt J, Comet I . EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas. Nat Med. 2017; 23(4):483-492. DOI: 10.1038/nm.4293. View

11.

Boyer L, Plath K, Zeitlinger J, Brambrink T, Medeiros L, Lee T . Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature. 2006; 441(7091):349-53. DOI: 10.1038/nature04733. View

12.

Bracken A, Dietrich N, Pasini D, Hansen K, Helin K . Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. Genes Dev. 2006; 20(9):1123-36. PMC: 1472472. DOI: 10.1101/gad.381706. View

13.

Mikkelsen T, Ku M, Jaffe D, Issac B, Lieberman E, Giannoukos G . Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature. 2007; 448(7153):553-60. PMC: 2921165. DOI: 10.1038/nature06008. View

14.

Mohn F, Weber M, Rebhan M, Roloff T, Richter J, Stadler M . Lineage-specific polycomb targets and de novo DNA methylation define restriction and potential of neuronal progenitors. Mol Cell. 2008; 30(6):755-66. DOI: 10.1016/j.molcel.2008.05.007. View

15.

Agger K, Cloos P, Rudkjaer L, Williams K, Andersen G, Christensen J . The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A-ARF locus in response to oncogene- and stress-induced senescence. Genes Dev. 2009; 23(10):1171-6. PMC: 2685535. DOI: 10.1101/gad.510809. View

16.

Barradas M, Anderton E, Carlos Acosta J, Li S, Banito A, Rodriguez-Niedenfuhr M . Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS. Genes Dev. 2009; 23(10):1177-82. PMC: 2685533. DOI: 10.1101/gad.511109. View

17.

Berg T, Thoene S, Yap D, Wee T, Schoeler N, Rosten P . A transgenic mouse model demonstrating the oncogenic role of mutations in the polycomb-group gene EZH2 in lymphomagenesis. Blood. 2014; 123(25):3914-24. DOI: 10.1182/blood-2012-12-473439. View

18.

Hosogane M, Funayama R, Nishida Y, Nagashima T, Nakayama K . Ras-induced changes in H3K27me3 occur after those in transcriptional activity. PLoS Genet. 2013; 9(8):e1003698. PMC: 3757056. DOI: 10.1371/journal.pgen.1003698. View

19.

Kaneda A, Fujita T, Anai M, Yamamoto S, Nagae G, Morikawa M . Activation of Bmp2-Smad1 signal and its regulation by coordinated alteration of H3K27 trimethylation in Ras-induced senescence. PLoS Genet. 2011; 7(11):e1002359. PMC: 3207904. DOI: 10.1371/journal.pgen.1002359. View

20.

Kondo Y, Shen L, Cheng A, Ahmed S, Boumber Y, Charo C . Gene silencing in cancer by histone H3 lysine 27 trimethylation independent of promoter DNA methylation. Nat Genet. 2008; 40(6):741-50. DOI: 10.1038/ng.159. View