Title: Epigenetic dysregulation by nickel through repressive chromatin domain disruption.
Authors: Jose, Cynthia C; Xu, Beisi; Jagannathan, Lakshmanan; Trac, Candi; Mallela, Ramya K; Hattori, Takamitsu; Lai, Darson; Koide, Shohei; Schones, Dustin E; Cuddapah, Suresh
Published In Proc Natl Acad Sci U S A, (2014 Oct 07)
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.
PubMed ID: 25246589
MeSH Terms: Acetylation; Amino Acid Sequence; Binding Sites/genetics; Blotting, Western; Bronchi/cytology; CCCTC-Binding Factor; Cell Line; Chromatin/genetics; Chromatin/metabolism*; Epigenesis, Genetic/drug effects*; Epigenesis, Genetic/genetics; Epithelial Cells/drug effects*; Epithelial Cells/metabolism; Gene Expression Profiling; Genome, Human/genetics; Histones/metabolism; Humans; Lysine/metabolism; Methylation; Nickel/pharmacology*; Oligonucleotide Array Sequence Analysis; Promoter Regions, Genetic/genetics; Protein Binding/drug effects; RNA Interference; Repressor Proteins/genetics; Repressor Proteins/metabolism