ATRX: the case of a peculiar chromatin remodeler

Abstract

The SWI/SNF-like chromatin remodeler ATRX has recently garnered renewed attention. ATRX mutations were first identified in patients bearing the syndrome after which it is named, alpha thalassemia/mental retardation, X-linked. While ATRX has long been implicated in transcriptional regulation through multiple mechanisms, recent studies have identified a role for ATRX in the regulation of histone variant deposition. In addition, current reports describe ATRX to be mutated at high percentages in multiple tumor types, suggestive of a potential 'driver' role in cancer. Here we discuss the numerous and seemingly diverse roles for ATRX in transcriptional regulation and histone deposition and suggest that ATRX's effects are mediated by its regulation of histones within the chromatin template.

Keywords: ATRX; histone variants; macroH2A and H3.3; telomeres; α-globin.

Figure 1. ATRX is a multidomain-containing chromatin remodeler. The ADD domain of ATRX (dark blue box) contains both a GATA-like domain and a PHD and “reads” the H3K9me3 modification.^,- We reported the in vivo interaction between the N-terminal 841 amino acids of ATRX with macroH2A1 (dashed red line). ATRX interacts with HP1α via a PxVxL motif present in the indicated region (orange box). Of note, while the interaction between EZH2 and ATRX (hatched blue box) was detected by yeast two hybrid, it remains to be seen if this persists in vivo and if indeed the entire region depicted is required for this interaction.

Figure 2. Hypothetical models for ATRX-mediated histone exchange and transcriptional activation of the α-globin gene cluster. (A) ATRX facilitates activation via the nucleosomal eviction of macroH2A1 and/or the Daxx mediated incorporation of H3.3 into nucleosomes potentially switching between “ON” and “OFF” chromatin states. (B) ATRX loads CTCF and resolves repressive G4 DNA structures at tandem repeats (TRs) to permit gene activation at the α-globin cluster. Shown is a 50kb UCSC genome browser snapshot of the α-globin cluster. ChIP-sequencing data plots of macroH2A1 (K562 cells, green) and ATRX (primary erythroblasts, blue) are overlaid (scales are 70 and 600 respectively). Below the panel, genes are presented in black, ATRX associated tandem repeat tracks in blue and CTCF associated sites from genome wide ChIA-PET analysis (K562 cells) in orange. All three CTCF sites overlap ATRX peaks and two of these occur at TRs. Of note, the ChIP-sequencing data presented were obtained from cell lines with different expression levels of α-globin (primary erythroblasts express α-globin at much higher levels than K562⁵⁷) and the association of macroH2A1 and ATRX with the locus are likely reflective of the differences in α-globin transcription between these two cell types.