Tcra enhancer activation by inducible transcription factors downstream of pre-TCR signaling.

The Journal of Immunology : Official Journal of the American Association of Immunologists
Beatriz del BlancoCristina Hernández-Munain

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 dict...Continue Reading

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Citations

Nov 22, 2012·Proceedings of the National Academy of Sciences of the United States of America·Han-Yu ShihMichael S Krangel
Nov 19, 2013·Nucleic Acids Research·Trevor Siggers, Raluca Gordân
Apr 2, 2015·Proceedings of the National Academy of Sciences of the United States of America·Beatriz del BlancoCristina Hernández-Munain
Mar 17, 2019·The Journal of Immunology : Official Journal of the American Association of Immunologists·Alonso Rodríguez-CaparrósCristina Hernández-Munain
Feb 26, 2020·Journal of Cell Science·Silvia Prieto-SánchezCarlos Suñé
Nov 15, 2020·International Journal of Molecular Sciences·Alonso Rodríguez-CaparrósCristina Hernández-Munain

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