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Tcf1 regulates T lymphocyte lineage fidelity through its target genes Gata3 and Bcl11b

ABSTRACT: T cell factor 1 (Tcf1) is the first T cell‒specific protein induced in multipotent progenitors following Notch signaling in the thymus, leading to the activation of two major target genes, Gata3 and Bcl11b. Tcf1 deficiency results in partial arrests in T cell development high apoptosis, and increased development of B cells and myeloid cells. Phenotypically, fully T cell‒committed, Tcf1-deficient thymocytes have promiscuous gene expression, an altered epigenetic profile and can de-differentiate into more immature thymocytes and non-T cells. Expressing Bcl11b in Tcf1-deficient cells rescues T cell development, but does not strongly suppress the development of non-T cells; in contrast, expressing Gata3 suppresses the development of non-T cells, but does not rescue T cell development. Thus, T cell development is controlled by a minimal transcription factor network involving Notch signaling, Tcf1, and the subsequent division of labor between Bcl11b and Gata3, thereby ensuring a properly regulated T cell gene expression program

ORGANISM(S): Mus musculus

PROVIDER: GSE119469 | GEO | 2019/08/28

REPOSITORIES: GEO

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GATA3 restrains Notch signaling activity and represses NK cell development to induce human T cell commitment following Notch-induced T-lineage specification (ChIP-Seq)

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2016-04-06 | E-GEOD-71751 | biostudies-arrayexpress

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2020-05-26 | GSE129853 | GEO

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2016-02-12 | E-GEOD-73239 | biostudies-arrayexpress

Distinct Notch1 and BCL11B requirements mediate human γδ/αβ T cell development [BCL11B_ex vivo]

Project description:Notch-dependent BCL11B induction converts thymus seeding precursor cells into committed T cell progenitors that subsequently differentiate into T cells bearing either the γδ or αβ T cell receptor. In human, strong Notch activation favors γδ T cell development at the expense of αβ-lineage differentiation, but the underlying molecular mechanism has remained unclear. Therefore, we performed paired mRNA and miRNA profiling across 11 stages of human T cell development, including developing γδ T cells. We identify the miR-17-92 cluster as a direct Notch target and show that miR-17 promotes human TCRγδ T cell development by targeting BCL11B, a gene required for αβ but not for γδ T cell development. Thus, following its role as a licensing factor to induce BCL11B expression in early T cell precursors, Notch activation limits BCL11B expression through miR-17 until thymocytes have passed the β-selection checkpoint when Notch activation is turned off. Hereby Notch prevents premature BCL11B upregulation that is required for αβ-lineage differentiation and this results in preferential γδ-lineage differentiation. Our work unravels a dual role for Notch in controlling BCL11B expression during intrathymic differentiation and provides a unique resource for understanding the mRNA/miRNA interactions that control human T cell development. We used microarrays in order to profile the gene expression in 11 ex vivo T cell subsets, isolated from human thymus. Cord blood CD34+Lin- HPCs were used as a reference subset for extrathymic HPCs.

2020-05-26 | GSE129852 | GEO

Distinct Notch1 and BCL11B requirements mediate human γδ/αβ T cell development [miRNA BCL11B_coculture]

Project description:Notch-dependent BCL11B induction converts thymus seeding precursor cells into committed T cell progenitors that subsequently differentiate into T cells bearing either the γδ or αβ T cell receptor. In human, strong Notch activation favors γδ T cell development at the expense of αβ-lineage differentiation, but the underlying molecular mechanism has remained unclear. Therefore, we performed paired mRNA and miRNA profiling across 11 stages of human T cell development, including developing γδ T cells. We identify the miR-17-92 cluster as a direct Notch target and show that miR-17 promotes human TCRγδ T cell development by targeting BCL11B, a gene required for αβ but not for γδ T cell development. Thus, following its role as a licensing factor to induce BCL11B expression in early T cell precursors, Notch activation limits BCL11B expression through miR-17 until thymocytes have passed the β-selection checkpoint when Notch activation is turned off. Hereby Notch prevents premature BCL11B upregulation that is required for αβ-lineage differentiation and this results in preferential γδ-lineage differentiation. Our work unravels a dual role for Notch in controlling BCL11B expression during intrathymic differentiation and provides a unique resource for understanding the mRNA/miRNA interactions that control human T cell development. The expression of 756 miRNAs was determined using the Taqman stem-loop RT-qPCR method as previously described (Mets E. Leukemia. 2015, Mavrakis KJ. Nat Genet. 2011).

2020-05-26 | GSE129855 | GEO

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Project description:Notch-dependent BCL11B induction converts thymus seeding precursor cells into committed T cell progenitors that subsequently differentiate into T cells bearing either the γδ or αβ T cell receptor. In human, strong Notch activation favors γδ T cell development at the expense of αβ-lineage differentiation, but the underlying molecular mechanism has remained unclear. Therefore, we performed paired mRNA and miRNA profiling across 11 stages of human T cell development, including developing γδ T cells. We identify the miR-17-92 cluster as a direct Notch target and show that miR-17 promotes human TCRγδ T cell development by targeting BCL11B, a gene required for αβ but not for γδ T cell development. Thus, following its role as a licensing factor to induce BCL11B expression in early T cell precursors, Notch activation limits BCL11B expression through miR-17 until thymocytes have passed the β-selection checkpoint when Notch activation is turned off. Hereby Notch prevents premature BCL11B upregulation that is required for αβ-lineage differentiation and this results in preferential γδ-lineage differentiation. Our work unravels a dual role for Notch in controlling BCL11B expression during intrathymic differentiation and provides a unique resource for understanding the mRNA/miRNA interactions that control human T cell development. The expression of 756 miRNAs and 3 small RNA controls was determined using the Taqman stem-loop RT-qPCR method as previously described (Mets E. Leukemia. 2015, Mavrakis KJ. Nat Genet. 2011).

2020-05-26 | GSE129854 | GEO

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2016-02-12 | E-GEOD-73238 | biostudies-arrayexpress

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