Régulation de l'expression du gène T-bet pendant la différenciation des cellules th1 chez l'homme

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Integration of distinct intracellular signaling pathways at distal regulatory elements directs T-bet expression in human CD4+ T cells.

International audienceT-bet is a key regulator controlling Th1 cell development. This factor is not expressed in naive CD4(+) T cells, and the mechanisms controlling expression of T-bet are incompletely understood. In this study, we defined regulatory elements at the human T-bet locus and determined how signals originating at the TCR and at cytokine receptors are integrated to induce chromatin modifications and expression of this gene during human Th1 cell differentiation. We found that T cell activation induced two strong DNase I-hypersensitive sites (HS) and rapid histone acetylation at these elements in CD4(+) T cells. Histone acetylation and T-bet expression were strongly inhibited by cyclosporine A, and we detected binding of NF-AT to a HS in vivo. IL-12 and IFN-gamma signaling alone were not sufficient to induce T-bet expression in naive CD4(+) T cells, but enhanced T-bet expression in TCR/CD28-stimulated cells. We detected a third HS 12 kb upstream of the mRNA start site only in developing Th1 cells, which was bound by IL-12-induced STAT4. Our data suggest that T-bet locus remodeling and gene expression are initiated by TCR-induced NF-AT recruitment and amplified by IL-12-mediated STAT4 binding to distinct distal regulatory elements during human Th1 cell differentiation

Chromosome-scale assembly of the yellow mealworm genome

International audienceBackground: The yellow mealworm beetle, $Tenebrio\ molitor$ , is a promising alternative protein source for animal and human nutrition and its farming involves relatively low environmental costs. For these reasons, its industrial scale production started this century. However, to optimize and breed sustainable new $T.\ molitor$ lines, the access to its genome remains essential. Methods: By combining Oxford Nanopore and Illumina Hi-C data, we constructed a high-quality chromosome-scale assembly of $T.\ molitor$ . Then, we combined RNA-seq data and available coleoptera proteomes for gene prediction with GMOVE. Results: We produced a high-quality genome with a N50 = 21.9Mb with a completeness of 99.5% and predicted 21,435 genes with a median size of 1,780 bp. Gene orthology between $T.\ molitor$ and $Tribolium\ castaneum$ showed a highly conserved synteny between the two coleoptera and paralogs search revealed an expansion of histones in the $T.\ molitor$ genome. Conclusions: The present genome will greatly help fundamental and applied research such as genetic breeding and will contribute to the sustainable production of the yellow mealworm

Chromatin remodeling by the SWI/SNF-like BAF complex and STAT4 activation synergistically induce IL-12Rbeta2 expression during human Th1 cell differentiation.

Interleukin-12 (IL-12) is a key cytokine for the development of T helper type 1 (Th1) responses; however, naive CD4(+) T cells do not express IL-12Rbeta2, and are therefore unresponsive to IL-12. We have examined the mechanisms that control Th1-specific expression of the human IL-12Rbeta2 gene at early time points after T-cell stimulation. We have identified a Th1-specific enhancer element that binds signal transducer and activator of transcription 4 (STAT4) in vivo in developing Th1 but not Th2 cells. T-cell receptor (TCR) signaling induced histone hyperacetylation and recruitment of BRG1, the ATPase subunit of the SWI/SNF-like BAF chromatin remodeling complex, to the IL-12Rbeta2 regulatory regions and was associated with low-level gene transcription at the IL-12Rbeta2 locus. However, high-level IL-12Rbeta2 expression required TCR triggering in the presence of IL-12. Our results indicate a synergistic role of TCR-induced chromatin remodeling and cytokine-induced STAT4 activation to direct IL-12Rbeta2 expression during Th1 cell development