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del Blanco B , Garcia-Mariscal A , Wiest DL , Hernandez-Munain C
Tcra Enhancer Activation by Inducible Transcription Factors Downstream of Pre-TCR Signaling
Journal of Immunology. 2012 Apr;188(7) :3278-3293
PMID: WOS:000302150300042   
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The Tcra enhancer (E alpha) is essential for pre-TCR-mediated activation of germline transcription and V(D)J recombination. E alpha is considered an archetypical enhanceosome that acts through the functional synergy and cooperative binding of multiple transcription factors. Based on dimethylsulfate genomic footprinting experiments, there has been a long-standing paradox regarding E alpha activation in the absence of differences in enhancer occupancy. Our data provide the molecular mechanism of E alpha activation and an explanation of this paradox. We found that germline transcriptional activation of Tcra is dependent on constant phospholipase C gamma, as well as calcineurin- and MAPK/ERK-mediated signaling, indicating that inducible transcription factors are crucially involved. NFAT, AP-1, and early growth response factor 1, together with CREB-binding protein/p300 coactivators, bind to E alpha as part of an active enhanceosome assembled during pre-TCR signaling. We favor a scenario in which the binding of lymphoid-restricted and constitutive transcription factors to E alpha prior to its activation forms a regulatory scaffold to recruit factors induced by pre-TCR signaling. Thus, the combinatorial assembly of tissue-and signal-specific transcription factors dictates the E alpha function. This mechanism for enhancer activation may represent a general paradigm in tissue-restricted and stimulus-responsive gene regulation. The Journal of Immunology, 2012, 188: 3278-3293.
del Blanco, Beatriz Garcia-Mariscal, Alberto Wiest, David L. Hernandez-Munain, Cristina Spanish Ministry of Science and Innovation[BFU2009-08796, BFU2005-01715/BCM]; Junta de Andalucia[CTS-6587, CVI-4526]; Consejo Superior de Investigaciones Cientificas[201020E060]; European Regional Development Fund This work was supported by Spanish Ministry of Science and Innovation Grant BFU2009-08796, Junta de Andalucia Grants CTS-6587 and CVI-4526, and Consejo Superior de Investigaciones Cientificas Grant 201020E060. This work was partly supported by the European Regional Development Fund. B.d.B. was partly supported by a predoctoral grant for formation of research personnel (FPI program) from the Spanish Ministry of Science and Innovation (BFU2005-01715/BCM). 82 Amer assoc immunologists Bethesda 917cp