PT - JOURNAL ARTICLE AU - David Valle-Garcìa AU - Domhnall S. McHugh AU - Zulekha A. Qadeer AU - Flávia G. Ghiraldini AU - Dan Hasson AU - Michael A. Dyer AU - Félix Recillas-Targa AU - Emily Bernstein TI - ATRX binds to atypical chromatin domains at the 3’ exons of ZNF genes to preserve H3K9me3 enrichment AID - 10.1101/027789 DP - 2015 Jan 01 TA - bioRxiv PG - 027789 4099 - http://biorxiv.org/content/early/2015/09/29/027789.short 4100 - http://biorxiv.org/content/early/2015/09/29/027789.full AB - ATRX is a SWI/SNF chromatin remodeler proposed to govern genomic stability through the regulation of repetitive sequences such as rDNA, retrotransposons, and pericentromeric and telomeric repeats. However, few direct ATRX target genes have been identified and high-throughput genomic approaches are currently lacking for ATRX. Here we present a comprehensive ChIP-sequencing study of ATRX in the human erythroleukemic cell line K562, in which we identify the 3’ exons of zinc finger genes (ZNFs) as a new class of ATRX targets. These 3’ exonic regions encode the zinc finger motifs, which can range from 1-40 copies per ZNF gene and share large stretches of sequence similarity. These regions often contain an atypical chromatin signature: they are transcriptionally active, contain high levels of H3K36me3 and are paradoxically enriched in H3K9me3. We find that these ZNF 3’ exons are also co-occupied by SETDB1, TRIM28 and ZNF274. CRISPR/Cas9-mediated loss-of-function studies demonstrate a significant reduction of H3K9me3 at the ZNF 3’ exons in the absence of ATRX and that H3K9me3 levels at atypical chromatin regions are particularly sensitive to ATRX loss compared to other H3K9me3-occupied regions. As ZNFs are one of the most rapidly expanding gene families in primates and genomic rearrangements are believed to be responsible for ZNF duplications, our results suggest that ATRX binds to the 3’ exons of ZNFs to maintain their genomic stability through preservation of H3K9me3.