Long-Range Enhancer Interactions Are Prevalent in Mouse Embryonic Stem Cells and Are Reorganized upon Pluripotent State Transition

Clara Lopes Novo,Biola-Maria Javierre,Jonathan Cairns,Anne Segonds-Pichon,Steven W Wingett,Paula Freire-Pritchett,Mayra Furlan-Magaril,Stefan Schoenfelder,Peter Fraser,Peter J Rugg-Gunn

doi:10.1016/j.celrep.2018.02.040

Clara Lopes Novo, Biola-Maria Javierre + Show 8 more

Open Access

https://doi.org/10.1016/j.celrep.2018.02.040

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Abstract

SummaryTranscriptional enhancers, including super-enhancers (SEs), form physical interactions with promoters to regulate cell-type-specific gene expression. SEs are characterized by high transcription factor occupancy and large domains of active chromatin, and they are commonly assigned to target promoters using computational predictions. How promoter-SE interactions change upon cell state transitions, and whether transcription factors maintain SE interactions, have not been reported. Here, we used promoter-capture Hi-C to identify promoters that interact with SEs in mouse embryonic stem cells (ESCs). We found that SEs form complex, spatial networks in which individual SEs contact multiple promoters, and a rewiring of promoter-SE interactions occurs between pluripotent states. We also show that long-range promoter-SE interactions are more prevalent in ESCs than in epiblast stem cells (EpiSCs) or Nanog-deficient ESCs. We conclude that SEs form cell-type-specific interaction networks that are partly dependent on core transcription factors, thereby providing insights into the gene regulatory organization of pluripotent cells.

Highlights

Complex, multi-layered compaction and folding enables the eukaryotic genome to undergo functional organization within the 3D nuclear space
Promoter-SE interactions frequently spanned large distances (>800 kb) in embryonic stem cells (ESCs), but not in epiblast stem cells (EpiSCs) or in Nanog-deficient ESCs. These results provide insights into the organization of chromatin topology in ESCs and lead to a better understanding of how gene regulatory networks can switch between pluripotent states
SEs Are Highly Interactive Hubs in ESCs To map the gene promoters that are in close physical proximity to SEs in mouse ESCs, we performed Promotercapture Hi-C (PCHi-C), a high-throughput 3C-based technique with a capture step to enrich for interactions at >22,000 promoters at single-restriction-fragment resolution (Mifsud et al, 2015; Schoenfelder et al, 2015a)

Summary

Introduction

Multi-layered compaction and folding enables the eukaryotic genome to undergo functional organization within the 3D nuclear space. Intra-TAD DNA loops are typically cell-type specific and are frequently rewired upon cell state changes (Smith et al, 2016; Denholtz et al, 2013; Schoenfelder et al, 2015b; Freire-Pritchett et al, 2017). This hierarchical nuclear organization permits the coordinated activation and repression of cell-identity genes while restricting the pool of promoters that are able to contact regulatory elements, including transcriptional enhancers (Dixon et al, 2012)

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