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CTCF-binding sites demarcate chromatin domains enriched with H3K9me2 or H3K9me3 and restrict the spreading of these histone modifications in human cells

ABSTRACT: CTCF-binding sites are frequently found at the boundaries of chromatin domains enriched with specific histone modifications in vertebrate genomes, where they function as barriers that limit the spreading of these modifications. However, the role of CTCF-binding sites in chromatin domains marked by H3K9me2 or H3K9me3 remains poorly understood. In this study, we analyzed CTCF-binding sites and the distribution of H3K9me2 and H3K9me3 around these sites in human K562 cells, and investigated the spreading of these modifications following CTCF depletion. Genome-wide analysis revealed that certain CTCF-binding sites are located at the boundaries of chromatin domains enriched with H3K9me2 or H3K9me3. Upon loss of CTCF binding, both modifications spread to neighboring chromatin at over half of boundaries delimiting highly and distinctly enriched domains. Boundaries where such spreading did not occur (non-spreading boundaries) were flanked by regions with a more active chromatin state compared to those where spreading occurred (spreading boundaries). Gene transcription was significantly reduced in neighboring regions where H3K9me2 or H3K9me3 had spread. Further comprehensive analysis revealed that this transcriptional reduction was specifically associated with the spread of H3K9me2 rather than H3K9me3. These findings suggest that CTCF-binding sites demarcate chromatin domains enriched with H3K9me2 or H3K9me3 and act as barriers to the propagation of these modifications in mammalian cells. Notably, the spread of H3K9me2 appears to play a specific role in transcriptional repression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE298130 | GEO | 2026/04/26

REPOSITORIES: GEO

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Project description: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. 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-spreadingM-bM-^@M-^Sassociated gene silencing. These results have major implications in understanding H3K9me2 dynamics and the consequences of chromatin domain disruption during pathogenesis.

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CTCF-binding sites demarcate chromatin domains enriched with H3K9me2 or H3K9me3 and restrict the spreading of these histone modifications in human cells

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