title: Epigenetic dysregulation by nickel through repressive chromatin domain disruption.
abstract: Investigations into the genomic landscape of histone modifications in heterochromatic regions have revealed histone H3 lysine 9 dimethylation (H3K9me2) to be important for differentiation and maintaining cell identity. H3K9me2 is associated with gene silencing and is organized into large repressive domains that exist in close proximity to active genes, indicating the importance of maintenance of proper domain structure. Here we show that nickel, a nonmutagenic environmental carcinogen, disrupted H3K9me2 domains, resulting in the spreading of H3K9me2 into active regions, which was associated with gene silencing. We found weak CCCTC-binding factor (CTCF)-binding sites and reduced CTCF binding at the Ni-disrupted H3K9me2 domain boundaries, suggesting a loss of CTCF-mediated insulation function as a potential reason for domain disruption and spreading. We furthermore show that euchromatin islands, local regions of active chromatin within large H3K9me2 domains, can protect genes from H3K9me2-spreading-associated gene silencing. These results have major implications in understanding H3K9me2 dynamics and the consequences of chromatin domain disruption during pathogenesis.
authors.affiliation: Department of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987;
authors.forename: Cynthia C
authors.initials: CC
authors.lastname: Jose
authors.affiliation: Department of Cancer Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010;
authors.forename: Beisi
authors.initials: B
authors.lastname: Xu
authors.affiliation: Department of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987;
authors.forename: Lakshmanan
authors.initials: L
authors.lastname: Jagannathan
authors.affiliation: Department of Cancer Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010;
authors.forename: Candi
authors.initials: C
authors.lastname: Trac
authors.affiliation: Department of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987;
authors.forename: Ramya K
authors.initials: RK
authors.lastname: Mallela
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637.
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Hattori
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637.
authors.forename: Darson
authors.initials: D
authors.lastname: Lai
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637.
authors.forename: Shohei
authors.initials: S
authors.lastname: Koide
authors.affiliation: Department of Cancer Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010; Irell and Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA 91010; and suresh.cuddapah@nyumc.org dschones@coh.org.
authors.forename: Dustin E
authors.initials: DE
authors.lastname: Schones
authors.affiliation: Department of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987; suresh.cuddapah@nyumc.org dschones@coh.org.
authors.forename: Suresh
authors.initials: S
authors.lastname: Cuddapah
mesh_terms: D000107:Acetylation; D000595:Amino Acid Sequence; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D001980:Bronchi / Q000166:cytology; D000076246:CCCTC-Binding Factor; D002460:Cell Line; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic / Q000187:drug effects* / Q000235:genetics; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D020869:Gene Expression Profiling; D015894:Genome, Human / Q000235:genetics; D006657:Histones / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D009532:Nickel / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D002843:Chromatin; D006657:Histones; D012097:Repressor Proteins; D009532:Nickel; D008239:Lysine
keywords: insulator; nickel carcinogenesis; nickel toxicity