Cohesin promotes stochastic domain intermingling to ensure proper regulation of boundary-proximal genes
Open Access
- 22 June 2020
- journal article
- research article
- Published by Springer Nature in Nature Genetics
- Vol. 52 (8), 840-848
- https://doi.org/10.1038/s41588-020-0647-9
Abstract
The human genome can be segmented into topologically associating domains (TADs), which have been proposed to spatially sequester genes and regulatory elements through chromatin looping. Interactions between TADs have also been suggested, presumably because of variable boundary positions across individual cells. However, the nature, extent and consequence of these dynamic boundaries remain unclear. Here, we combine high-resolution imaging with Oligopaint technology to quantify the interaction frequencies across both weak and strong boundaries. We find that chromatin intermingling across population-defined boundaries is widespread but that the extent of permissibility is locus-specific. Cohesin depletion, which abolishes domain formation at the population level, does not induce ectopic interactions but instead reduces interactions across all boundaries tested. In contrast, WAPL or CTCF depletion increases inter-domain contacts in a cohesin-dependent manner. Reduced chromatin intermingling due to cohesin loss affects the topology and transcriptional bursting frequencies of genes near boundaries. We propose that cohesin occasionally bypasses boundaries to promote incorporation of boundary-proximal genes into neighboring domains.Funding Information
- U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (R35GM128903)
This publication has 59 references indexed in Scilit:
- TANGO: a generic tool for high-throughput 3D image analysis for studying nuclear organizationBioinformatics, 2013
- An integrated encyclopedia of DNA elements in the human genomeNature, 2012
- Topological domains in mammalian genomes identified by analysis of chromatin interactionsNature, 2012
- Spatial partitioning of the regulatory landscape of the X-inactivation centreNature, 2012
- Integrative genomics viewerNature Biotechnology, 2011
- Chromosome TerritoriesCold Spring Harbor Perspectives in Biology, 2010
- Comprehensive Mapping of Long-Range Interactions Reveals Folding Principles of the Human GenomeScience, 2009
- Transcriptional Dysregulation in NIPBL and Cohesin Mutant Human CellsPLoS Biology, 2009
- On the Molecular Etiology of Cornelia de Lange SyndromeAnnals of the New York Academy of Sciences, 2008
- CTCF mediates long-range chromatin looping and local histone modification in the β-globin locusGenes & Development, 2006