Impact of 3-dimensional genome organization, guided by cohesin and CTCF looping, on sex-biased chromatin interactions and gene expression in mouse liver

Background: Sex differences in the transcriptome and epigenome are widespread in mouse liver and are associated with sex-bias in liver disease. Several thousand sex-differential distal enhancers have been identified; however, their links to sex-biased genes and the impact of any sex-differences in nuclear organization, DNA looping, and chromatin interactions are unknown. Results: To address these issues, we first characterized 1,847 mouse liver genomic regions showing significant sex differential occupancy by cohesin and CTCF, two key 3D nuclear organizing factors. These sex-differential binding sites were largely distal to sex-biased genes, but rarely generated sex-differential TAD (topologically associating domain) or intra-TAD loop anchors. A substantial subset of the sex-biased cohesin-non-CTCF binding sites, but not the sex-biased cohesin-and-CTCF binding sites, overlapped sex-biased enhancers. Cohesin depletion reduced the expression of male-biased genes with distal, but not proximal, sex-biased enhancers by >10-fold, implicating cohesin in long-range enhancer interactions regulating sex-biased genes. Using circularized chromosome conformation capture-based sequencing (4C-seq), we showed that sex differences in distal sex...Continue Reading