TY - JOUR T1 - Cohesin promotes interactions across domain boundaries to regulate gene expression JF - bioRxiv DO - 10.1101/649335 SP - 649335 AU - Jennifer M. Luppino AU - Son C. Nguyen AU - Daniel S. Park AU - Yemin Lan AU - Zhuxuan Xu AU - Eric F. Joyce Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/05/31/649335.abstract N2 - The mammalian genome has been segmented into thousands of topologically associated domains (TADs) based on chromosome conformation capture studies, such as Hi-C. TADs have been proposed to act as insulated neighborhoods, spatially sequestering and insulating the enclosed genes and regulatory elements through self-association and chromatin looping. Recent results indicate that inter-TAD interactions can also occur. However, the nature, extent, and function of these inter-TAD interactions remains unclear. Here, we combine Hi-C data with Oligopaint technology to precisely visualize neighboring TADs and quantify their interaction frequency in human cells. We find that intra-TAD interactions are indeed more enriched than inter-TAD interactions. However, we also observe extensive intermingling between neighboring domains in the majority of cells. Moreover, we find that cohesin depletion, which is known to abolish TADs at the population-average level, does not induce ectopic interactions but instead reduces interactions between neighboring domains. We find that cohesin loss preferentially alters locus topology and transcriptional bursting frequencies at genes close to domain boundaries, potentially explaining the gene expression changes observed in the cohesinopathy Cornelia de Lange syndrome. Together, our results challenge the notion that cohesin forms spatially insulated domains to regulate gene expression. Instead, we propose that cohesin normally antagonizes domain insulation by frequently bypassing boundaries to promote proper gene regulation at a subset of boundary-proximal genes. ER -