ena-STUDY-EMBL-09-10-2017-08:37:21:717-543
CTCF-Mediated Chromatin Loops between Promoter and Gene Body Regulate Alternative Splicing across Individuals
The CCCTC-binding factor (CTCF) is known to establish long-range DNA contacts that alter the three-dimensional architecture of chromatin, but how the presence of CTCF influences nearby gene expression is still poorly understood. Here, we analyze CTCF ChIP-seq, RNA-seq, and Hi-C data, together with genotypes from a healthy human cohort, and measure statistical associations between inter-individual variability in CTCF binding and alternative exon usage. We demonstrate that CTCF-mediated chromatin loops between promoters and intragenic regions are prevalent and that when exons are in physical proximity with their promoters, CTCF binding correlates with exon inclusion in spliced mRNA. Genome wide, CTCF-bound exons are enriched for genes involved in signalling and cellular stress-response pathways. Structural analysis of three specific examples, checkpoint kinase 2 (Chk2), CDC-like kinase 3 (Clk3), and histone-lysine N-methyltransferase (EHMT1), suggests that CTCF-mediated exon inclusion is likely to down-regulate enzyme activity by disrupting annotated protein domains. In total, our study suggests that alternative exon usage is regulated by CTCF-dependent chromatin structure.
The CCCTC-binding factor (CTCF) is known to establish long-range DNA contacts that alter the three-dimensional architecture of chromatin, but how the presence of CTCF influences nearby gene expression is still poorly understood. Here, we analyze CTCF ChIP-seq, RNA-seq, and Hi-C data, together with genotypes from a healthy human cohort, and measure statistical associations between inter-individual variability in CTCF binding and alternative exon usage. We demonstrate that CTCF-mediated chromatin loops between promoters and intragenic regions are prevalent and that when exons are in physical proximity with their promoters, CTCF binding correlates with exon inclusion in spliced mRNA. Genome wide, CTCF-bound exons are enriched for genes involved in signalling and cellular stress-response pathways. Structural analysis of three specific examples, checkpoint kinase 2 (Chk2), CDC-like kinase 3 (Clk3), and histone-lysine N-methyltransferase (EHMT1), suggests that CTCF-mediated exon inclusion is likely to down-regulate enzyme activity by disrupting annotated protein domains. In total, our study suggests that alternative exon usage is regulated by CTCF-dependent chromatin structure.