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Cell Rep. 2016 Jun 7;15(10):2159-2169. doi: 10.1016/j.celrep.2016.04.087. Epub 2016 May 26.

Active and Inactive Enhancers Cooperate to Exert Localized and Long-Range Control of Gene Regulation.

Author information

1
Department of Pathology, NYU School of Medicine, New York, NY 10016, USA.
2
Department of Pathology, NYU School of Medicine, New York, NY 10016, USA; Department of Biology, NYU, New York, NY 10003, USA.
3
Department of Pathology, NYU School of Medicine, New York, NY 10016, USA; Department of Biology, NYU, New York, NY 10003, USA; Center for Health Informatics and Bioinformatics, NYU School of Medicine, New York, NY 10016, USA.
4
Department of Pathology, Yale University, New Haven, CT 06510, USA.
5
Department of Biology, NYU, New York, NY 10003, USA; Department of Computer Science, Courant Institute of Mathematical Sciences, NYU, New York, NY 10003, USA; Simons Center for Data Analysis, New York, NY 10010, USA.
6
Department of Pathology, NYU School of Medicine, New York, NY 10016, USA. Electronic address: jane.skok@med.nyu.edu.

Abstract

V(D)J recombination relies on the presence of proximal enhancers that activate the antigen receptor (AgR) loci in a lineage- and stage-specific manner. Unexpectedly, we find that both active and inactive AgR enhancers cooperate to disseminate their effects in a localized and long-range manner. Here, we demonstrate the importance of short-range contacts between active enhancers that constitute an Igk super-enhancer in B cells. Deletion of one element reduces the interaction frequency between other enhancers in the hub, which compromises the transcriptional output of each component. Furthermore, we establish that, in T cells, long-range contact and cooperation between the inactive Igk enhancer MiEκ and the active Tcrb enhancer Eβ alters enrichment of CBFβ binding in a manner that impacts Tcrb recombination. These findings underline the complexities of enhancer regulation and point to a role for localized and long-range enhancer-sharing between active and inactive elements in lineage- and stage-specific control.

KEYWORDS:

Igk; Tcrb; enhancer-sharing; gene regulation; localized and long-range contacts; nuclear architecture; super-enhancer; transcription factor binding; transcriptional output

PMID:
27239026
PMCID:
PMC4899175
DOI:
10.1016/j.celrep.2016.04.087
[Indexed for MEDLINE]
Free PMC Article

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