Foxp3 Exploits a Pre-Existent Enhancer Landscape for Regulatory T Cell Lineage Specification

• Published in: Cell 2012-09, Vol.151 (1), p.153-166
• Main Authors: Samstein, Robert M., Arvey, Aaron, Josefowicz, Steven Z., Peng, Xiao, Reynolds, Alex, Sandstrom, Richard, Neph, Shane, Sabo, Peter, Kim, Jeong M., Liao, Will, Li, Ming O., Leslie, Christina, Stamatoyannopoulos, John A., Rudensky, Alexander Y.
• Format: Article
• Language: English
• Subjects: Animals; CD4-Positive T-Lymphocytes - metabolism; Cell Differentiation; chromatin; Chromatin - metabolism; Enhancer Elements, Genetic; Female; Forkhead Box Protein O1; Forkhead Transcription Factors - metabolism; genes; homeostasis; Lymphocyte Activation; Mice; Specific Pathogen-Free Organisms; T-lymphocytes; T-Lymphocytes, Regulatory - cytology; T-Lymphocytes, Regulatory - metabolism; transcription factors
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2012.06.053

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. [Display omitted] ► Treg cell specification factor Foxp3 binds to preaccessible enhancer ► Foxp3 binds to sites occupied by cofactors in precursor cell ► Structural homolog Foxo1 serves as a Foxp3 predecessor in precursor cells ► TCR activation confers accessibility to the majority of Treg-specific enhancers The transcription factor Foxp3, which specifies regulatory T cell fate, promotes differentiation not by making chromatin more accessible to specific factors but instead by modifying transcriptional activity at pre-existing enhancers, which are already accessible due to the binding of cofactors and paralogs in precursor cells.