Home LiteratureArticle Details
PMID: 25417162 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

ATRX directs binding of PRC2 to Xist RNA and Polycomb targets.

Cell ·Vol. 159 ·No. 4 ·2014-11-06 ·Pages 869-83

Sarma K, Cifuentes-Rojas C, Ergun A, Del Rosario A, Jeon Y, White F, Sadreyev R, Lee JT

Abstract

X chromosome inactivation (XCI) depends on the long noncoding RNA Xist and its recruitment of Polycomb Repressive Complex 2 (PRC2). PRC2 is also targeted to other sites throughout the genome to effect transcriptional repression. Using XCI as a model, we apply an unbiased proteomics approach to isolate Xist and PRC2 regulators and identified ATRX. ATRX unexpectedly functions as a high-affinity RNA-binding protein that directly interacts with RepA/Xist RNA to promote loading of PRC2 in vivo. Without ATRX, PRC2 cannot load onto Xist RNA nor spread in cis along the X chromosome. Moreover, epigenomic profiling reveals that genome-wide targeting of PRC2 depends on ATRX, as loss of ATRX leads to spatial redistribution of PRC2 and derepression of Polycomb responsive genes. Thus, ATRX is a required specificity determinant for PRC2 targeting and function.

MeSH Terms
Animals DNA Helicases/isolation & purification,metabolism Embryonic Stem Cells/metabolism Female Male Mice Nuclear Proteins/isolation & purification,metabolism Polycomb Repressive Complex 2/metabolism RNA, Long Noncoding/metabolism X Chromosome Inactivation X-linked Nuclear Protein
Chemicals
Nuclear Proteins RNA, Long Noncoding XIST non-coding RNA Polycomb Repressive Complex 2 DNA Helicases Atrx protein, mouse X-linked Nuclear Protein
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Sarma Kavitha
Howard Hughes Medical Institute; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA USA; Department of Genetics, Harvard Medical School, Boston, MA USA.
Cifuentes-Rojas Catherine
Howard Hughes Medical Institute; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA USA; Department of Genetics, Harvard Medical School, Boston, MA USA.
Ergun Ayla
Department of Molecular Biology, Massachusetts General Hospital, Boston, MA USA; Department of Genetics, Harvard Medical School, Boston, MA USA.
Del Rosario Amanda
Department of Bioengineering, Massachusetts Institute of Technology, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA USA.
Jeon Yesu
Howard Hughes Medical Institute; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA USA; Department of Genetics, Harvard Medical School, Boston, MA USA.
White Forest
Department of Bioengineering, Massachusetts Institute of Technology, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA USA.
Sadreyev Ruslan
Department of Molecular Biology, Massachusetts General Hospital, Boston, MA USA; Department of Genetics, Harvard Medical School, Boston, MA USA; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA.
Lee Jeannie T
Howard Hughes Medical Institute; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA USA; Department of Genetics, Harvard Medical School, Boston, MA USA; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA. Electronic address: [email protected].
References (59)
59 references, click to expand
  1. ATP-dependent roX RNA remodeling by the helicase maleless enables specific association of MSL proteins.
    Mol Cell. 2013 Jul 25;51(2):174-84 PMID: 23870143
  2. Epigenetic regulation by long noncoding RNAs.
    Science. 2012 Dec 14;338(6113):1435-9 PMID: 23239728
  3. Chromatin proteins and modifications as drug targets.
    Nature. 2013 Oct 24;502(7472):480-8 PMID: 24153301
  4. Promiscuous RNA binding by Polycomb repressive complex 2.
    Nat Struct Mol Biol. 2013 Nov;20(11):1250-7 PMID: 24077223
  5. PRC2 binds active promoters and contacts nascent RNAs in embryonic stem cells.
    Nat Struct Mol Biol. 2013 Nov;20(11):1258-64 PMID: 24141703
  6. Molecular characterization of EGFR and EGFRvIII signaling networks in human glioblastoma tumor xenografts.
    Mol Cell Proteomics. 2012 Dec;11(12):1724-40 PMID: 22964225
  7. Spreading of X chromosome inactivation via a hierarchy of defined Polycomb stations.
    Genome Res. 2012 Oct;22(10):1864-76 PMID: 22948768
  8. ATRX: the case of a peculiar chromatin remodeler.
    Epigenetics. 2013 Jan;8(1):3-9 PMID: 23249563
  9. Occupying chromatin: Polycomb mechanisms for getting to genomic targets, stopping transcriptional traffic, and staying put.
    Mol Cell. 2013 Mar 7;49(5):808-24 PMID: 23473600
  10. X-inactivation, imprinting, and long noncoding RNAs in health and disease.
    Cell. 2013 Mar 14;152(6):1308-23 PMID: 23498939
  11. Jpx RNA activates Xist by evicting CTCF.
    Cell. 2013 Jun 20;153(7):1537-51 PMID: 23791181
  12. Different flavors of X-chromosome inactivation in mammals.
    Curr Opin Cell Biol. 2013 Jun;25(3):314-21 PMID: 23578369
  13. Computer aided manual validation of mass spectrometry-based proteomic data.
    Methods. 2013 Jun 15;61(3):219-26 PMID: 23500044
  14. Tandem stem-loops in roX RNAs act together to mediate X chromosome dosage compensation in Drosophila.
    Mol Cell. 2013 Jul 25;51(2):156-73 PMID: 23870142
  15. High-resolution Xist binding maps reveal two-step spreading during X-chromosome inactivation.
    Nature. 2013 Dec 19;504(7480):465-9 PMID: 24162848
  16. Interactions between JARID2 and noncoding RNAs regulate PRC2 recruitment to chromatin.
    Mol Cell. 2014 Jan 23;53(2):290-300 PMID: 24374312
  17. Jarid2 Is Implicated in the Initial Xist-Induced Targeting of PRC2 to the Inactive X Chromosome.
    Mol Cell. 2014 Jan 23;53(2):301-16 PMID: 24462204
  18. Regulatory interactions between RNA and polycomb repressive complex 2.
    Mol Cell. 2014 Jul 17;55(2):171-85 PMID: 24882207
  19. The chromatin remodeller ATRX: a repeat offender in human disease.
    Trends Biochem Sci. 2013 Sep;38(9):461-6 PMID: 23916100
  20. X-chromosome hyperactivation in mammals via nonlinear relationships between chromatin states and transcription.
    Nat Struct Mol Biol. 2012 Jan;19(1):56-61 PMID: 22139016
  21. Chromosomal silencing and localization are mediated by different domains of Xist RNA.
    Nat Genet. 2002 Feb;30(2):167-74 PMID: 11780141
  22. The ATRX syndrome protein forms a chromatin-remodeling complex with Daxx and localizes in promyelocytic leukemia nuclear bodies.
    Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10635-40 PMID: 12953102
  23. A novel transcription regulatory complex containing death domain-associated protein and the ATR-X syndrome protein.
    J Biol Chem. 2004 May 7;279(19):20369-77 PMID: 14990586
  24. The human XIST gene: analysis of a 17 kb inactive X-specific RNA that contains conserved repeats and is highly localized within the nucleus.
    Cell. 1992 Oct 30;71(3):527-42 PMID: 1423611
  25. XIST RNA paints the inactive X chromosome at interphase: evidence for a novel RNA involved in nuclear/chromosome structure.
    J Cell Biol. 1996 Feb;132(3):259-75 PMID: 8636206
  26. Specific interaction between the XNP/ATR-X gene product and the SET domain of the human EZH2 protein.
    Hum Mol Genet. 1998 Apr;7(4):679-84 PMID: 9499421
  27. Histone macroH2A1 is concentrated in the inactive X chromosome of female mammals.
    Nature. 1998 Jun 11;393(6685):599-601 PMID: 9634239
  28. Tsix, a gene antisense to Xist at the X-inactivation centre.
    Nat Genet. 1999 Apr;21(4):400-4 PMID: 10192391
  29. Multiple spatially distinct types of facultative heterochromatin on the human inactive X chromosome.
    Proc Natl Acad Sci U S A. 2004 Dec 14;101(50):17450-5 PMID: 15574503
  30. A transient heterochromatic state in Xist preempts X inactivation choice without RNA stabilization.
    Mol Cell. 2006 Mar 3;21(5):617-28 PMID: 16507360
  31. Loss of Atrx affects trophoblast development and the pattern of X-inactivation in extraembryonic tissues.
    PLoS Genet. 2006 Apr;2(4):e58 PMID: 16628246
  32. 14-3-3sigma controls mitotic translation to facilitate cytokinesis.
    Nature. 2007 Mar 15;446(7133):329-32 PMID: 17361185
  33. Poly(ADP-ribose) polymerase 1 is inhibited by a histone H2A variant, MacroH2A, and contributes to silencing of the inactive X chromosome.
    J Biol Chem. 2007 Apr 27;282(17):12851-9 PMID: 17322296
  34. Perinucleolar targeting of the inactive X during S phase: evidence for a role in the maintenance of silencing.
    Cell. 2007 May 18;129(4):693-706 PMID: 17512404
  35. Mutations in the chromatin-associated protein ATRX.
    Hum Mutat. 2008 Jun;29(6):796-802 PMID: 18409179
  36. Intersection of the RNA interference and X-inactivation pathways.
    Science. 2008 Jun 6;320(5881):1336-41 PMID: 18535243
  37. Determinants for association and guide RNA-directed endonuclease cleavage by purified RNA editing complexes from Trypanosoma brucei.
    J Mol Biol. 2008 Aug 1;381(1):35-48 PMID: 18572190
  38. Polycomb proteins targeted by a short repeat RNA to the mouse X chromosome.
    Science. 2008 Oct 31;322(5902):750-6 PMID: 18974356
  39. A proximal conserved repeat in the Xist gene is essential as a genomic element for X-inactivation in mouse.
    Development. 2009 Jan;136(1):139-46 PMID: 19036803
  40. A new model for random X chromosome inactivation.
    Development. 2009 Jan;136(1):1-10 PMID: 19036804
  41. Design and analysis of ChIP-seq experiments for DNA-binding proteins.
    Nat Biotechnol. 2008 Dec;26(12):1351-9 PMID: 19029915
  42. ATRX marks the inactive X chromosome (Xi) in somatic cells and during imprinted X chromosome inactivation in trophoblast stem cells.
    Chromosoma. 2009 Apr;118(2):209-22 PMID: 19005673
  43. Biochemical mechanisms of gene regulation by polycomb group protein complexes.
    Curr Opin Genet Dev. 2009 Apr;19(2):150-8 PMID: 19345089
  44. Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression.
    Proc Natl Acad Sci U S A. 2009 Jul 14;106(28):11667-72 PMID: 19571010
  45. 2-D structure of the A region of Xist RNA and its implication for PRC2 association.
    PLoS Biol. 2010 Jan;8(1):e1000276 PMID: 20052282
  46. Distinct factors control histone variant H3.3 localization at specific genomic regions.
    Cell. 2010 Mar 5;140(5):678-91 PMID: 20211137
  47. Global survey of escape from X inactivation by RNA-sequencing in mouse.
    Genome Res. 2010 May;20(5):614-22 PMID: 20363980
  48. Short RNAs are transcribed from repressed polycomb target genes and interact with polycomb repressive complex-2.
    Mol Cell. 2010 Jun 11;38(5):675-88 PMID: 20542000
  49. Daxx is an H3.3-specific histone chaperone and cooperates with ATRX in replication-independent chromatin assembly at telomeres.
    Proc Natl Acad Sci U S A. 2010 Aug 10;107(32):14075-80 PMID: 20651253
  50. ATR-X syndrome protein targets tandem repeats and influences allele-specific expression in a size-dependent manner.
    Cell. 2010 Oct 29;143(3):367-78 PMID: 21029860
  51. The long noncoding RNA, Jpx, is a molecular switch for X chromosome inactivation.
    Cell. 2010 Oct 29;143(3):390-403 PMID: 21029862
  52. Genome-wide identification of polycomb-associated RNAs by RIP-seq.
    Mol Cell. 2010 Dec 22;40(6):939-53 PMID: 21172659
  53. The ATRX-ADD domain binds to H3 tail peptides and reads the combined methylation state of K4 and K9.
    Hum Mol Genet. 2011 Jun 1;20(11):2195-203 PMID: 21421568
  54. Functional significance of mutations in the Snf2 domain of ATRX.
    Hum Mol Genet. 2011 Jul 1;20(13):2603-10 PMID: 21505078
  55. YY1 tethers Xist RNA to the inactive X nucleation center.
    Cell. 2011 Jul 8;146(1):119-33 PMID: 21729784
  56. Combinatorial readout of histone H3 modifications specifies localization of ATRX to heterochromatin.
    Nat Struct Mol Biol. 2011 Jul;18(7):777-82 PMID: 21666677
  57. ATRX ADD domain links an atypical histone methylation recognition mechanism to human mental-retardation syndrome.
    Nat Struct Mol Biol. 2011 Jul;18(7):769-76 PMID: 21666679
  58. Gene silencing in X-chromosome inactivation: advances in understanding facultative heterochromatin formation.
    Nat Rev Genet. 2011 Aug;12(8):542-53 PMID: 21765457
  59. The Xist RNA A-repeat comprises a novel AUCG tetraloop fold and a platform for multimerization.
    RNA. 2011 Nov;17(11):1973-82 PMID: 21947263
Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2014.10.019
Email
[email protected]
Published
2014-11-06
Pages
869-83
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC4379047
Subset
IM
Grants
NIGMS NIH HHS · F32-GM101828 · United States
NIDDK NIH HHS · P30 DK040561 · United States
NIGMS NIH HHS · F32 GM090765 · United States
NIGMS NIH HHS · R01-GM090278 · United States
NIGMS NIH HHS · R01 GM090278 · United States
NIGMS NIH HHS · F32 GM101828 · United States
NIGMS NIH HHS · F32-GM090765 · United States
Corrections
ErratumIn
-
ErratumIn
-
External Links
PubMed source DOI: 10.1016/j.cell.2014.10.019 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2