Duality of enhancer functioning mode revealed in a reduced TCR beta gene enhancer knockin mouse model

The Journal of Immunology : Official Journal of the American Association of Immunologists
Marie BonnetSalvatore Spicuglia

Abstract

The TCRbeta gene enhancer (Ebeta) commands TCRbeta gene expression through the lifespan of T lymphocytes. Genetic and molecular studies have implied that in early thymocytes, Ebeta directs chromatin opening over the Dbeta-Jbeta-Cbeta domains and triggers initial Dbeta-Jbeta recombination. In mature T cells, Ebeta is required for expression of the assembled TCRbeta gene. Whether these separate activities rely on distinct Ebeta regulatory sequences and involve differing modes of activation is unclear. Using gene targeting in mouse embryonic stem cells, we replaced Ebeta by a conserved core fragment (Ebeta169). We found that Ebeta169-carrying alleles were capable of sustaining beta gene expression and the development of mature T cells in homozygous knockin mice. Surprisingly, these procedures and underlying molecular transactions were affected to a wide range of degrees depending on the developmental stage. Early thymocytes barely achieved Dbeta-Jbeta germline transcription and recombination. In contrast, T cells displayed substantial though heterogeneous levels of VDJ-rearranged TCRbeta gene expression. Our results have implications regarding enhancer function in cells of the adaptive immune system and, potentially, TCRbeta gene ...Continue Reading

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Citations

Sep 16, 2010·Genome Research·Aleksandra PekowskaSalvatore Spicuglia
Jun 24, 2017·The Journal of Immunology : Official Journal of the American Association of Immunologists·Jiang-Yang ZhaoEugene M Oltz
Nov 28, 2017·Frontiers in Immunology·Marie BonnetJocelyne Demengeot
Aug 19, 2011·The EMBO Journal·Aleksandra PekowskaSalvatore Spicuglia
Feb 24, 2012·The Journal of Immunology : Official Journal of the American Association of Immunologists·Beatriz del BlancoCristina Hernández-Munain
Mar 4, 2015·The Journal of Immunology : Official Journal of the American Association of Immunologists·Joaquin Zacarías-CabezaSalvatore Spicuglia
Nov 15, 2020·International Journal of Molecular Sciences·Alonso Rodríguez-CaparrósCristina Hernández-Munain

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