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Based on dimethylsulfate genomic footprinting experiments, there has been a long-standing paradox regarding E\u03b1 activation in the absence of differences in enhancer occupancy. Our data provide the molecular mechanism of E\u03b1 activation and an explanation of this paradox. We found that germline transcriptional activation of Tcra is dependent on constant phospholipase C\u03b3, 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\u03b1 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\u03b1 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\u03b1 function. This mechanism for enhancer activation may represent a general paradigm in tissue-restricted and stimulus-responsive gene regulation.<\/jats:p>","DOI":"10.4049\/jimmunol.1100271","type":"journal-article","created":{"date-parts":[[2012,2,23]],"date-time":"2012-02-23T06:50:53Z","timestamp":1329979853000},"page":"3278-3293","source":"Crossref","is-referenced-by-count":23,"title":["<i>Tcra<\/i> Enhancer Activation by Inducible Transcription Factors Downstream of Pre-TCR Signaling"],"prefix":"10.1093","volume":"188","author":[{"given":"Beatriz","family":"del Blanco","sequence":"first","affiliation":[{"name":"Departamento de Biolog\u00eda Celular e Inmunolog\u00eda, Instituto de Parasitolog\u00eda y Biomedicina \u201cL\u00f3pez-Neyra\u201d (IPBLN-CSIC), Consejo Superior de Investigaciones Cient\u00edficas , 18100-Armilla, Granada ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Garc\u00eda-Mariscal","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda Celular e Inmunolog\u00eda, Instituto de Parasitolog\u00eda y Biomedicina \u201cL\u00f3pez-Neyra\u201d (IPBLN-CSIC), Consejo Superior de Investigaciones Cient\u00edficas , 18100-Armilla, Granada ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David L","family":"Wiest","sequence":"additional","affiliation":[{"name":"Fox Chase Cancer Center , Philadelphia, PA 19111"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Hern\u00e1ndez-Munain","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda Celular e Inmunolog\u00eda, Instituto de Parasitolog\u00eda y Biomedicina \u201cL\u00f3pez-Neyra\u201d (IPBLN-CSIC), Consejo Superior de Investigaciones Cient\u00edficas , 18100-Armilla, Granada ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2012,4,1]]},"reference":[{"key":"2025032409595136100_r1","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.immuni.2005.11.012","article-title":"Developmental and molecular characterization of emerging \u03b2- and \u03b3\u03b4-selected pre-T cells in the adult mouse thymus","volume":"24","author":"Taghon","year":"2006","journal-title":"Immunity"},{"key":"2025032409595136100_r2","doi-asserted-by":"crossref","first-page":"5230","DOI":"10.4049\/jimmunol.172.9.5230","article-title":"Obligatory role for cooperative signaling by pre-TCR and Notch during thymocyte differentiation","volume":"172","author":"Ciofani","year":"2004","journal-title":"J. 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