Promoter-Enhancer Communication Occurs Primarily within Insulated Neighborhoods

• Published in: Molecular cell Vol. 73; no. 2; pp. 250 - 263.e5
• Main Authors: Sun, Fei, Chronis, Constantinos, Kronenberg, Michael, Chen, Xiao-Fen, Su, Trent, Lay, Fides D., Plath, Kathrin, Kurdistani, Siavash K., Carey, Michael F.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.01.2019
• Subjects: Animals; Binding Sites; CCCTC-Binding Factor - genetics; CCCTC-Binding Factor - metabolism; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line; chromatin looping; Chromosomal Proteins, Non-Histone - genetics; Chromosomal Proteins, Non-Histone - metabolism; Chromosomes, Mammalian; Cohesins; Databases, Genetic; Down-Regulation; enhancer; Enhancer Elements, Genetic; Esrrb; insulated neighborhood; Insulator Elements; Mice; Mouse Embryonic Stem Cells - physiology; promoter; Promoter Regions, Genetic; Protein Binding; Receptors, Estrogen - genetics; Receptors, Estrogen - metabolism; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; transcription; Transcription, Genetic; enhancer; promoter; chromatin looping; transcription; Esrrb; insulated neighborhood
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2018.10.039

Metazoan chromosomes are sequentially partitioned into topologically associating domains (TADs) and then into smaller sub-domains. One class of sub-domains, insulated neighborhoods, are proposed to spatially sequester and insulate the enclosed genes through self-association and chromatin looping. However, it has not been determined functionally whether promoter-enhancer interactions and gene regulation are broadly restricted to within these loops. Here, we employed published datasets from murine embryonic stem cells (mESCs) to identify insulated neighborhoods that confine promoter-enhancer interactions and demarcate gene regulatory regions. To directly address the functionality of these regions, we depleted estrogen-related receptor β (Esrrb), which binds the Mediator co-activator complex, to impair enhancers of genes within 222 insulated neighborhoods without causing mESC differentiation. Esrrb depletion reduces Mediator binding, promoter-enhancer looping, and expression of both nascent RNA and mRNA within the insulated neighborhoods without significantly affecting the flanking genes. Our data indicate that insulated neighborhoods represent functional regulons in mammalian genomes. [Display omitted] •Promoters interact with loci within CTCF-cohesin-demarcated insulated neighborhoods•Esrrb knockdown inactivates enhancers by removing mediator from them in mESCs•Enhancer inactivation disrupts promoter-enhancer looping•Enhancer inactivation downregulates genes only within insulated neighborhoods Sun et al. report that a class of chromosomal sub-domains, “insulated neighborhoods,” broadly constrains communication between a promoter and its enhancers or other elements. Enhancer inactivation by depleting the transcription factor Esrrb downregulates genes within insulated neighborhoods without affecting flanking genes, indicating that these sub-domains constrain enhancer action and represent functional regulons.