Epigenetic Repogramming by an Environmental Carcinogen Through Chromatin Domain Disruption

This SuperSeries is composed of the SubSeries listed below. Histone modifications associated with gene silencing typically mark large contiguous regions of the genome forming repressive chromatin domain structures. Since the repressive domains exist in close proximity to active regions, maintenance of domain structure is critically important. This study shows that nickel, a nonmutagenic carcinogen, can disrupt histone H3 lysine 9 dimethylation (H3K9me2) domain structures genome-wide, resulting in spreading of H3K9me2 marks into the active regions, which is associated with gene silencing. Our results suggest inhibition of DNA binding of the insulator protein CCCTC-binding factor (CTCF) at the H3K9me2 domain boundaries as a potential reason for H3K9me2 domain disruption. These findings have major implications in understanding chromatin dynamics and the consequences of chromatin domain disruption during pathogenesis. Overall design: 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. Refer to individual Series