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PARP1- and CTCF-mediated interactions between active and repressed chromatin at the lamina promote oscillating transcription

ABSTRACT: Transcriptionally active and inactive chromatin domains tend to segregate into separate sub-nuclear compartments to maintain stable expression patterns. However, we have uncovered here an inter-chromosomal network connecting active loci enriched in circadian genes to repressed lamina-associated domains (LADs). The interactome is regulated by PARP1 and its co-factor, CTCF, which not only mediate chromatin fiber interactions, but also promote the recruitment of circadian genes to the lamina. Synchronization of circadian rhythm by serum shock induces oscillations in PARP1-CTCF interactions, which is accompanied by oscillating recruitment of circadian loci to the lamina, followed by the acquisition of repressive H3K9me2 marks and transcriptional attenuation. Furthermore, depletion of H3K9me2/3, inhibition of PARP activity by Olaparib or down-regulation of PARP1 or CTCF expression counteracts both recruitment to the envelope and circadian transcription. PARP1- and CTCF-regulated contacts between circadian loci and the repressive chromatin environment at the lamina thus mediate circadian transcriptional plasticity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE26880 | GEO | 2015/08/27

SECONDARY ACCESSION(S): PRJNA136121

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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PARP1- and CTCF-mediated interactions between active and repressed chromatin at the lamina promote oscillating transcription

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