title: Foxp3 exploits a pre-existent enhancer landscape for regulatory T cell lineage specification.
abstract: Regulatory T (Treg) cells, whose identity and function are defined by the transcription factor Foxp3, are indispensable for immune homeostasis. It is unclear whether Foxp3 exerts its Treg lineage specification function through active modification of the chromatin landscape and establishment of new enhancers or by exploiting a pre-existing enhancer landscape. Analysis of the chromatin accessibility of Foxp3-bound enhancers in Treg and Foxp3-negative T cells showed that Foxp3 was bound overwhelmingly to preaccessible enhancers occupied by its cofactors in precursor cells or a structurally related predecessor. Furthermore, the bulk of Foxp3-bound Treg cell enhancers lacking in Foxp3(-) CD4(+) cells became accessible upon T cell receptor activation prior to Foxp3 expression, and only a small subset associated with several functionally important genes were exclusively Treg cell specific. Thus, in a late cellular differentiation process, Foxp3 defines Treg cell functionality in an "opportunistic" manner by largely exploiting the preformed enhancer network instead of establishing a new enhancer landscape.
authors.affiliation: Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Samstein
authors.forename: Aaron
authors.initials: A
authors.lastname: Arvey
authors.forename: Steven Z
authors.initials: SZ
authors.lastname: Josefowicz
authors.forename: Xiao
authors.initials: X
authors.lastname: Peng
authors.forename: Alex
authors.initials: A
authors.lastname: Reynolds
authors.forename: Richard
authors.initials: R
authors.lastname: Sandstrom
authors.forename: Shane
authors.initials: S
authors.lastname: Neph
authors.forename: Peter
authors.initials: P
authors.lastname: Sabo
authors.forename: Jeong M
authors.initials: JM
authors.lastname: Kim
authors.forename: Will
authors.initials: W
authors.lastname: Liao
authors.forename: Ming O
authors.initials: MO
authors.lastname: Li
authors.forename: Christina
authors.initials: C
authors.lastname: Leslie
authors.forename: John A
authors.initials: JA
authors.lastname: Stamatoyannopoulos
authors.forename: Alexander Y
authors.initials: AY
authors.lastname: Rudensky
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002454:Cell Differentiation; D002843:Chromatin / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D013047:Specific Pathogen-Free Organisms; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000378:metabolism
chemical_list: D002843:Chromatin; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; C498833:Foxp3 protein, mouse