Disruption of ATRX-RNA interactions uncovers roles in ATRX localization and PRC2 function

Abstract

Heterochromatin in the eukaryotic genome is rigorously controlled by the concerted action of protein factors and RNAs. Here, we investigate the RNA binding function of ATRX, a chromatin remodeler with roles in silencing of repetitive regions of the genome and in recruitment of the polycomb repressive complex 2 (PRC2). We identify ATRX RNA binding regions (RBRs) and discover that the major ATRX RBR lies within the N-terminal region of the protein, distinct from its PHD and helicase domains. Deletion of this ATRX RBR (ATRXΔRBR) compromises ATRX interactions with RNAs in vitro and in vivo and alters its chromatin binding properties. Genome-wide studies reveal that loss of RNA interactions results in a redistribution of ATRX on chromatin. Finally, our studies identify a role for ATRX-RNA interactions in regulating PRC2 localization to a subset of polycomb target genes.

Cancer and Tumour Suppressor p53 Encounters at the Juncture of Sex Disparity

“…ATRX binding to XIST is essential for the recruitment of the polycomb repressive complex 2 (PRC2; Sarma et al, 2014 ), which in turn contributes to early gene repression events in XCI ( Bousard et al, 2019 ). Such tumour suppressive functions of ATRX are relevant to its mutation/loss across many cancer types ( Ren et al, 2020 ). What is of particular relevance to cancer sex disparity, is our finding that ATRX is among a set of X-linked genes connected to p53 functionally.…”

Non-Coding RNAs and Nucleosome Remodeling Complexes: An Intricate Regulatory Relationship

“…A final example involves the interaction with Xist and a less well-characterized nucleosome remodeler, ATRX. ATRX localizes to heterochromatic genomic regions via RNA interactions to modulate DNA methylation and/or nucleosome composition and exchanges histone H3 for the histone variant H3.3 [78,79]. ATRX interacts with Xist through a non-canonical RNA-binding domain, and this interaction is required for proper targeting of PRC2 to a subset of Polycomb target genes on Xi [79].…”

“…ATRX localizes to heterochromatic genomic regions via RNA interactions to modulate DNA methylation and/or nucleosome composition and exchanges histone H3 for the histone variant H3.3 [78,79]. ATRX interacts with Xist through a non-canonical RNA-binding domain, and this interaction is required for proper targeting of PRC2 to a subset of Polycomb target genes on Xi [79]. While examples of interactions between nucleosome remodelers and ncRNAs outside of BAF are less frequent at this time, this likely reflects the abundance for BAF-focused research in the field rather than BAF more often interacting with ncRNAs relative to other nucleosome remodelers.…”

“…Xist holds six repeating sequence elements (referred to as elements A-F) that mediate interactions with its binding partners. ATRX binds Xist repeat A with its N-terminal RNA binding domain (RBD) and its C-terminal helicase domain [79]. In comparison, Brg1 interacts with Xist repeats A, B, E, and F, though the domains or residues of Brg1 that mediate this interaction have not been determined [67].…”

Neurodevelopmental Disorders Caused by Defective Chromatin Remodeling: Phenotypic Complexity Is Highlighted by a Review of ATRX Function

“…Finally, ATRX has been shown to bind to the Xist lncRNA to promote recruitment of the PRC2 repressive complex and facilitate stable heterochromatin formation of the silenced X-chromosome (Sarma et al, 2014). RNA binding remains an understudied role for ATRX, although several reports have shown a range of interactions with multiple lncRNAs including TERRA (telomeric repeat-containing RNA) (Chu et al, 2017;Nguyen et al, 2017), ChRO1 in muscle (Park et al, 2018), and minor satellite RNAs at centromeric heterochromatin (Ren et al, 2020). These interactions are mediated through a unique N-terminal domain in ATRX to regulate differentiation, gene expression, DNA and histone methylation and chromatin compaction (Chu et al, 2017;Nguyen et al, 2017;Park et al, 2018;Ren et al, 2020).…”