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ATRX Directs Binding of PRC2 to Xist RNA and Polycomb Targets

Sarma, Kavitha, Cifuentes-Rojas, Catherine, Ergun, Ayla, del Rosario, Amanda, Jeon, Yesu, White, Forest, Sadreyev, Ruslan, Lee, Jeannie T.
Cell 2014 v.159 pp. 869-883
RNA-binding proteins, X chromosome, genes, models, non-coding RNA, proteomics, transcription (genetics)
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.