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A multiply redundant genetic switch 'locks in' the transcriptional signature of regulatory T cells
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A multiply redundant genetic switch 'locks in' the transcriptional signature of regulatory T cells
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Journal Article
A multiply redundant genetic switch 'locks in' the transcriptional signature of regulatory T cells
2012
Overview
Transcription factor Foxp3 is essential for the development and function of regulatory T cells, but it does not act in isolation. Benoist and colleagues identify a quintet of factors that facilitate transcriptional regulation by Foxp3.
The transcription factor Foxp3 participates dominantly in the specification and function of Foxp3
+
CD4
+
regulatory T cells (T
reg
cells) but is neither strictly necessary nor sufficient to determine the characteristic T
reg
cell signature. Here we used computational network inference and experimental testing to assess the contribution of other transcription factors to this. Enforced expression of Helios or Xbp1 elicited distinct signatures, but Eos, IRF4, Satb1, Lef1 and GATA-1 elicited exactly the same outcome, acting in synergy with Foxp3 to activate expression of most of the T
reg
cell signature, including key transcription factors, and enhancing occupancy by Foxp3 at its genomic targets. Conversely, the T
reg
cell signature was robust after inactivation of any single cofactor. A redundant genetic switch thus 'locked in' the T
reg
cell phenotype, a model that would account for several aspects of T
reg
cell physiology, differentiation and stability.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ Animals
/ Biomedical and Life Sciences
/ DNA-Binding Proteins - biosynthesis
/ DNA-Binding Proteins - genetics
/ Forkhead Transcription Factors - genetics
/ GATA1 Transcription Factor - genetics
/ Genetics
/ Humans
/ Ikaros Transcription Factor - biosynthesis
/ Ikaros Transcription Factor - genetics
/ Interferon Regulatory Factors - genetics
/ Lymphoid Enhancer-Binding Factor 1 - genetics
/ Matrix Attachment Region Binding Proteins - genetics
/ Mice
/ Regulatory Factor X Transcription Factors
/ Serine Endopeptidases - genetics
/ T cells
/ T-Lymphocytes, Regulatory - cytology
/ T-Lymphocytes, Regulatory - immunology
/ T-Lymphocytes, Regulatory - metabolism
/ Transcription Factors - biosynthesis
/ Transcription Factors - genetics
