A multiply redundant genetic switch 'locks in' the transcriptional signature of regulatory T cells
Copyright policy )A multiply redundant genetic switch 'locks in' the transcriptional signature of regulatory T cells
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.
- University of Illinois at Urbana Champaign United States
- Boston College United States
- Boehringer Ingelheim (Germany) Germany
- Boston University United States
- Institut de Pharmacologie Moléculaire et Cellulaire France
Transcription, Genetic, Lymphoid Enhancer-Binding Factor 1, Serine Endopeptidases, 610, Computational Biology, Cell Differentiation, Forkhead Transcription Factors, Regulatory Factor X Transcription Factors, Matrix Attachment Region Binding Proteins, Lymphocyte Activation, T-Lymphocytes, Regulatory, Article, DNA-Binding Proteins, Mice, Inbred C57BL, Ikaros Transcription Factor, Mice, CD4 Antigens, Interferon Regulatory Factors, Animals, Humans, GATA1 Transcription Factor, Transcription Factors
Transcription, Genetic, Lymphoid Enhancer-Binding Factor 1, Serine Endopeptidases, 610, Computational Biology, Cell Differentiation, Forkhead Transcription Factors, Regulatory Factor X Transcription Factors, Matrix Attachment Region Binding Proteins, Lymphocyte Activation, T-Lymphocytes, Regulatory, Article, DNA-Binding Proteins, Mice, Inbred C57BL, Ikaros Transcription Factor, Mice, CD4 Antigens, Interferon Regulatory Factors, Animals, Humans, GATA1 Transcription Factor, Transcription Factors
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