title: Tcra enhancer activation by inducible transcription factors downstream of pre-TCR signaling.
abstract: The Tcra enhancer (Eα) is essential for pre-TCR-mediated activation of germline transcription and V(D)J recombination. Eα 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 Eα activation in the absence of differences in enhancer occupancy. Our data provide the molecular mechanism of Eα activation and an explanation of this paradox. We found that germline transcriptional activation of Tcra is dependent on constant phospholipase Cγ, 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 Eα 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 Eα 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 Eα function. This mechanism for enhancer activation may represent a general paradigm in tissue-restricted and stimulus-responsive gene regulation.
authors.affiliation: Departamento de Biología Celular e Inmunología, Instituto de Parasitología y Biomedicina López-Neyra (IPBLN-CSIC), Consejo Superior de Investigaciones Científicas, 18100-Armilla, Granada, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: del Blanco
authors.forename: Alberto
authors.initials: A
authors.lastname: García-Mariscal
authors.forename: David L
authors.initials: DL
authors.lastname: Wiest
authors.forename: Cristina
authors.initials: C
authors.lastname: Hernández-Munain
mesh_terms: D000818:Animals; D001483:Base Sequence; D019703:Calcineurin / Q000502:physiology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D051766:Early Growth Response Protein 1 / Q000502:physiology; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation / Q000276:immunology*; D057809:HEK293 Cells; D006801:Humans; D019169:Jurkat Cells; D008223:Lymphoma / Q000473:pathology; D020935:MAP Kinase Signaling System; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes; D050778:NFATC Transcription Factors / Q000502:physiology; D051966:Phospholipase C gamma / Q000502:physiology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics*; D016415:Sequence Alignment; D012689:Sequence Homology, Nucleic Acid; D015398:Signal Transduction / Q000276:immunology*; D013953:Thymus Neoplasms / Q000473:pathology; D018808:Transcription Factor AP-1 / Q000502:physiology; D050880:p300-CBP Transcription Factors / Q000502:physiology
chemical_list: D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D046912:Multiprotein Complexes; D050778:NFATC Transcription Factors; D016693:Receptors, Antigen, T-Cell, alpha-beta; D018808:Transcription Factor AP-1; D050880:p300-CBP Transcription Factors; D019703:Calcineurin; D051966:Phospholipase C gamma