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Long-range chromosome interactions mediated by cohesin shape circadian gene expression [4C]

ABSTRACT: Mammalian circadian rhythm is established by the negative feedback loops consisting of a set of clock genes, which lead to the circadian expression of thousands of downstream genes. As genome-wide transcription is organized under the high-order chromosome structure, it is unclear how circadian gene expression is influenced by chromosome structure. In this study, we focus on the function of chromatin structure proteins cohesin as well as CTCF (CCCTC-binding factor) in circadian rhythm. We analyzed the interactome of a Bmal1-bound enhancer upstream of a clock gene, Nr1d1, by 4C-seq and observed that cohesin binding sites are enriched in the interactome. Integrating circadian transcriptome data and cistrome data, we found that cohesin-CTCF co-binding sites tend to insulate the phases of circadian oscillating genes while cohesin-non-CTCF sites facilitate the interaction between circadian enhancer and promoter. A coarse-grained model integrating the long-range effect of cohesin and CTCF markedly improved our mechanistic understanding of circadian gene expression. This model is subsequently supported by our RNA-seq data from cohesin knockout cells. Cohesin is required at least in part for driving the circadian gene expression by facilitating the enhancer-promoter looping. Taken together, our study provided a novel insight into the relationship between circadian transcriptome and the high-order chromosome structure.

ORGANISM(S): Mus musculus

PROVIDER: GSE68830 | GEO | 2016/04/04

SECONDARY ACCESSION(S): PRJNA283888

REPOSITORIES: GEO

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Project description:The spatial organization of genes in the interphase nucleus plays an important role in establishment and regulation of gene expression. The circadian expressed and clock controlled genes represent about 10% of the transcripts in the mammalian cells, however the role of genome topology in the expression of genes in a circadian manner remains to be elucidated. In this study we investigated the characteristics and dynamics of the genomic loci that contact the clock controlled gene Dbp during the circadian cycle. To do so, we combined genome-wide interaction profiling by chromosome conformation capture-on-chip (4C) technology with analyses of circadian gene expression in synchronized mouse embryonic fibroblasts (MEFs). This approach allowed us to elucidate the three-dimensional organization of the genome during the circadian cycle around the clock controlled gene Dbp, paralleling its circadian expression. We found that the Dbp genomic environment remains largely similar during the circadian cycle. However, specific DNA regions change their frequency of interaction with Dbp as the circadian cycle progresses, delineating a Dbp circadian interactome. These specific changes are not present in Bmal1-/- MEF, suggesting that the clock machinery is implicated in shaping the genomic landscape around the Dbp locus. The Dbp interactome is enriched in DNA elements related to the clock system (E boxes). We found a spatial clustering of functionally related genes. The Dbp circadian interactome contains a subset of circadian genes whose expression which closely parallel that for Dbp. Taken together, our results indicate that the Dbp subnuclear environment is organized to privilege the clock directed gene expression program. Wild type mouse embryonic fibroblasts at the circadian times (CT) 22, 26, 30, 34 and 46. Bmal1-/- mouse embrionic fibroblasts at CT 22 and CT 34 Biological replicate using an independent line of wild type mouse embrionic fibroblast at CT 22 and CT 34 This submission represents the chromosome conformation capture-on-chip component of the overall study

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Long-range chromosome interactions mediated by cohesin shape circadian gene expression [4C]

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