title: ATRX binds to atypical chromatin domains at the 3' exons of zinc finger genes to preserve H3K9me3 enrichment.
abstract: 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 multiple human cell lines, 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 co-occupied by SETDB1, TRIM28, and ZNF274, which form a complex with ATRX. CRISPR/Cas9-mediated loss-of-function studies demonstrate (i) a reduction of H3K9me3 at the ZNF 3' exons in the absence of ATRX and ZNF274 and, (ii) H3K9me3 levels at atypical chromatin regions are particularly sensitive to ATRX loss compared to other H3K9me3-occupied regions. As a consequence of ATRX or ZNF274 depletion, cells with reduced levels of H3K9me3 show increased levels of DNA damage, suggesting that ATRX binds to the 3' exons of ZNFs to maintain their genomic stability through preservation of H3K9me3.
authors.affiliation: a Departments of Oncological Sciences and Dermatology , Icahn School of Medicine at Mount Sinai , New York , NY , USA.|b Instituto de Fisiología Celular, Departamento de Genética Molecular, Universidad Nacional Autónoma de México , Ciudad de México , México.
authors.forename: David
authors.initials: D
authors.lastname: Valle-García
authors.affiliation: a Departments of Oncological Sciences and Dermatology , Icahn School of Medicine at Mount Sinai , New York , NY , USA.|c Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai , New York , NY , USA.
authors.forename: Zulekha A
authors.initials: ZA
authors.lastname: Qadeer
authors.affiliation: a Departments of Oncological Sciences and Dermatology , Icahn School of Medicine at Mount Sinai , New York , NY , USA.
authors.forename: Domhnall S
authors.initials: DS
authors.lastname: McHugh
authors.affiliation: a Departments of Oncological Sciences and Dermatology , Icahn School of Medicine at Mount Sinai , New York , NY , USA.
authors.forename: Flávia G
authors.initials: FG
authors.lastname: Ghiraldini
authors.affiliation: a Departments of Oncological Sciences and Dermatology , Icahn School of Medicine at Mount Sinai , New York , NY , USA.
authors.forename: Asif H
authors.initials: AH
authors.lastname: Chowdhury
authors.affiliation: a Departments of Oncological Sciences and Dermatology , Icahn School of Medicine at Mount Sinai , New York , NY , USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Hasson
authors.affiliation: d Department of Developmental Neurobiology , St Jude Children's Research Hospital , Memphis , Tennessee , USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Dyer
authors.affiliation: b Instituto de Fisiología Celular, Departamento de Genética Molecular, Universidad Nacional Autónoma de México , Ciudad de México , México.
authors.forename: Félix
authors.initials: F
authors.lastname: Recillas-Targa
authors.affiliation: a Departments of Oncological Sciences and Dermatology , Icahn School of Medicine at Mount Sinai , New York , NY , USA.|c Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai , New York , NY , USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Bernstein
mesh_terms: D024509:3' Flanking Region; D002460:Cell Line; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D005091:Exons; D042822:Genomic Instability; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000378:metabolism*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011496:Protein Methyltransferases / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D000076183:Tripartite Motif-Containing Protein 28; D000075924:X-linked Nuclear Protein; D016335:Zinc Fingers
chemical_list: D002843:Chromatin; D006657:Histones; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D012097:Repressor Proteins; C497246:ZNF274 protein, human; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C454062:SETDB1 protein, human; C101116:TRIM28 protein, human; D000076183:Tripartite Motif-Containing Protein 28; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein
keywords: ATRX; Atypical chromatin; ESET; H3K9me3; KAP1; KRAB-ZNFs; SETDB1; TRIM28; ZNF274; zinc finger genes