title: ATRX directs binding of PRC2 to Xist RNA and Polycomb targets.
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.
authors.affiliation: Howard Hughes Medical Institute; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA USA; Department of Genetics, Harvard Medical School, Boston, MA USA.
authors.forename: Kavitha
authors.initials: K
authors.lastname: Sarma
authors.affiliation: Howard Hughes Medical Institute; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA USA; Department of Genetics, Harvard Medical School, Boston, MA USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Cifuentes-Rojas
authors.affiliation: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA USA; Department of Genetics, Harvard Medical School, Boston, MA USA.
authors.forename: Ayla
authors.initials: A
authors.lastname: Ergun
authors.affiliation: Department of Bioengineering, Massachusetts Institute of Technology, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Del Rosario
authors.affiliation: Howard Hughes Medical Institute; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA USA; Department of Genetics, Harvard Medical School, Boston, MA USA.
authors.forename: Yesu
authors.initials: Y
authors.lastname: Jeon
authors.affiliation: Department of Bioengineering, Massachusetts Institute of Technology, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA USA.
authors.forename: Forest
authors.initials: F
authors.lastname: White
authors.affiliation: 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.
authors.forename: Ruslan
authors.initials: R
authors.lastname: Sadreyev
authors.affiliation: 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: lee@molbio.mgh.harvard.edu.
authors.forename: Jeannie T
authors.initials: JT
authors.lastname: Lee
mesh_terms: D000818:Animals; D004265:DNA Helicases / Q000302:isolation & purification / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000378:metabolism; D005260:Female; D008297:Male; D051379:Mice; D009687:Nuclear Proteins / Q000302:isolation & purification / Q000378:metabolism*; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism*; D062085:RNA, Long Noncoding / Q000378:metabolism*; D049951:X Chromosome Inactivation; D000075924:X-linked Nuclear Protein
chemical_list: D009687:Nuclear Proteins; D062085:RNA, Long Noncoding; C077885:XIST non-coding RNA; D063151:Polycomb Repressive Complex 2; D004265:DNA Helicases; C490462:Atrx protein, mouse; D000075924:X-linked Nuclear Protein