Global dynamics of stage-specific transcription factor binding during thymocyte development
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE107076 | GEO | 2018/04/04
REPOSITORIES: GEO
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Project description:T cell differentiation requires Notch1 signaling. Here we show that an enhancer upstream of Notch1 active in double-negative (DN) mouse thymocytes is responsible for raising Notch1 signaling intra-thymically. This enhancer is required to expand multipotent progenitors intra-thymically while delaying early differentiation until lineage restrictions are established. Early thymic progenitors lacking the enhancer show accelerated differentiation through the DN stages and increased frequency of B-, ILC-, and NK-cell differentiation. Transcription regulators for T cell lineage restriction and commitment are expressed normally, but ILC- and NK-cell gene expression persists after T cell lineage commitment and TCRb V-DJ recombination, Cd3 expression and b-selection are impaired. This Notch1 enhancer is inactive in double-positive (DP) thymocytes. Its aberrant reactivation at this stage in Ikaros mutants is required for leukemogenesis. Thus, the DN-specific Notch1 enhancer harnesses the regulatory architecture of DN and DP thymocytes to achieve carefully orchestrated changes in Notch1 signaling required for early lineage restrictions and normal T cell differentiation.
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Project description:Mouse thymocytes can be classified into four major subsets based on expression of CD4 and CD8 co-receptors. CD4-CD8- (double negative, DN) cells become CD4+CD8+ (double positive, DP) cells following productive T cell receptor (TCR) beta chain rearrangement. A small proportion of DP cells are selected through interaction of clonal TCRalpha/beta and MHC self peptide complex expressed on thymic stromal cells. DP cell expressing MHC class I-restricted TCR become CD4-CD8+ cells, which will finally differentiate into cytotoxic T cells, while MHC class II restricted selection generates CD4+CD8- helper lineage T cells. We used microarrays to identify genes important for thymocyte differentiation and lineage determination by profiling gene expression in different thymocyte subsets.
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Project description:T cell development proceeds in a series of developmental stages, which is precisely orchestrated by multiple signaling and molecular networks. Here we found a zinc finger protein Zfp335 intrinsically controls DN to DP transition, as T cell-specific deficiency in Zfp335 leads to a substantial accumulation of DN3 along with reduction of DP, CD4+ and CD8+ thymocytes. This developmental blockade at DN stage results from the impaired intracellular TCRβ expression as well as increased susceptibility to apoptosis in thymocytes. Transcriptomic and ChIP-seq analyses revealed a direct regulation of transcription factors Bcl6 and Rorc by Zfp335. Importantly, enhanced expression of TCRβ and Bcl6/RorγT restores the developmental defect during DN3 to DN4 transition and improves thymocytes survival, respectively. These findings identify a critical role of Zfp335 in controlling T cell development by maintaining intracellular TCR expression-mediated β-selection and independently activating cell survival signaling.
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