title: Active and Inactive Enhancers Cooperate to Exert Localized and Long-Range Control of Gene Regulation.
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.
authors.affiliation: Department of Pathology, NYU School of Medicine, New York, NY 10016, USA.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Proudhon
authors.affiliation: Department of Pathology, NYU School of Medicine, New York, NY 10016, USA.
authors.forename: Valentina
authors.initials: V
authors.lastname: Snetkova
authors.affiliation: Department of Pathology, NYU School of Medicine, New York, NY 10016, USA; Department of Biology, NYU, New York, NY 10003, USA.
authors.forename: Ramya
authors.initials: R
authors.lastname: Raviram
authors.affiliation: Department of Pathology, NYU School of Medicine, New York, NY 10016, USA.
authors.forename: Camille
authors.initials: C
authors.lastname: Lobry
authors.affiliation: 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.
authors.forename: Sana
authors.initials: S
authors.lastname: Badri
authors.affiliation: Department of Pathology, Yale University, New Haven, CT 06510, USA.
authors.forename: Tingting
authors.initials: T
authors.lastname: Jiang
authors.affiliation: Department of Pathology, NYU School of Medicine, New York, NY 10016, USA.
authors.forename: Bingtao
authors.initials: B
authors.lastname: Hao
authors.affiliation: Department of Pathology, NYU School of Medicine, New York, NY 10016, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Trimarchi
authors.affiliation: Department of Pathology, Yale University, New Haven, CT 06510, USA.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Kluger
authors.affiliation: Department of Pathology, NYU School of Medicine, New York, NY 10016, USA.
authors.forename: Iannis
authors.initials: I
authors.lastname: Aifantis
authors.affiliation: 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.
authors.forename: Richard
authors.initials: R
authors.lastname: Bonneau
authors.affiliation: Department of Pathology, NYU School of Medicine, New York, NY 10016, USA. Electronic address: jane.skok@med.nyu.edu.
authors.forename: Jane A
authors.initials: JA
authors.lastname: Skok
mesh_terms: D000818:Animals; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D008810:Mice, Inbred C57BL; D011485:Protein Binding / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D012333:RNA, Messenger; D016693:Receptors, Antigen, T-Cell, alpha-beta
keywords: Igk; Tcrb; enhancer-sharing; gene regulation; localized and long-range contacts; nuclear architecture; super-enhancer; transcription factor binding; transcriptional output