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T cell factor 1 is a gatekeeper for T-cell specification in response to Notch signaling

ABSTRACT: Although transcriptional programs associated with T-cell specification and commitment have been described, the functional hierarchy and the roles of key regulators in structuring/ orchestrating these programs remain unclear. Activation of Notch signaling in uncommitted precursors by the thymic stroma initiates the T-cell differentiation program. One regulator first induced in these precursors is the DNA binding protein Tcf-1, a T-cell specific mediator of Wnt signaling. Yet the specific contribution of Tcf-1 to early T-cell development and the signals inducing it in these cells remain unclear. Here we assign functional significance to Tcf-1 as a gatekeeper of T-cell fate. We show that Tcf-1 is directly activated by Notch signals. Tcf-1 is required at the earliest phase of Tcell determination for progression beyond the early thymic progenitor (ETP) stage. The global expression profile of Tcf-1 deficient progenitors indicates that basic processes of DNA metabolism are downregulated in its absence and the blocked T-cell progenitors become abortive and die by apoptosis. Our data thus add an important functional relationship to the roadmap of T-cell development. We used microarrays to detail the global programme of gene expression of mouse ETP thymocyte after Ikaros inactivation with dominant negative of Ik at different stage.

ORGANISM(S): Mus musculus

PROVIDER: GSE33513 | GEO | 2011/12/06

SECONDARY ACCESSION(S): PRJNA148813

REPOSITORIES: GEO

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T cell factor 1 is a gatekeeper for T-cell specification in response to Notch signaling

Project description:Although transcriptional programs associated with T-cell specification and commitment have been described, the functional hierarchy and the roles of key regulators in structuring/ orchestrating these programs remain unclear. Activation of Notch signaling in uncommitted precursors by the thymic stroma initiates the T-cell differentiation program. One regulator first induced in these precursors is the DNA binding protein Tcf-1, a T-cell specific mediator of Wnt signaling. Yet the specific contribution of Tcf-1 to early T-cell development and the signals inducing it in these cells remain unclear. Here we assign functional significance to Tcf-1 as a gatekeeper of T-cell fate. We show that Tcf-1 is directly activated by Notch signals. Tcf-1 is required at the earliest phase of Tcell determination for progression beyond the early thymic progenitor (ETP) stage. The global expression profile of Tcf-1 deficient progenitors indicates that basic processes of DNA metabolism are downregulated in its absence and the blocked T-cell progenitors become abortive and die by apoptosis. Our data thus add an important functional relationship to the roadmap of T-cell development. We used microarrays to detail the global programme of gene expression of mouse ETP thymocyte after Ikaros inactivation with dominant negative of Ik at different stage. 6 samples (mouse ETP thymocytes from wt, and Tcf1 inactivation) are analyzed Mouse Microarray Expression platforms, Affymetrix Mouse 430 2.0,

2011-12-06 | E-GEOD-33513 | biostudies-arrayexpress

Early innate lymphoid cell progenitor

Project description:We identified a new type of bone marrow progenitors termed early innate lymphoid cell progenitor (EILP) using TCF-1 GFP reporter mice. We compared the transcriptomes of early innate lymphoid cell progenitors (EILP) with other early progenitors, including HSC, LMPP, CMP, CLP, ETP and DN3.

2015-08-17 | GSE69789 | GEO

Bi-directional signaling by membrane-bound KitL induces proliferation and co-ordinates thymic endothelial cell and thymocyte expansion

Project description:The ligand for the c-Kit receptor, KitL, exists as a membrane-associated (mKitL) and a soluble form (sKitL). KitL functions outside c-Kit activation have not been identified. We show that co-culture of c-Kit– and mKitL–expressing NIH3T3 cells results in signaling through mKitL: c-Kit–bound mKitL recruits calcium-modulating cyclophilin ligand (CAML) to selectively activate Akt, leading to CREB phosphorylation, mTOR pathway activation, and increased cell proliferation. Activation of mKitL in thymic vascular endothelial cells (VECs) induces mKitL- and Akt-dependent proliferation, and genetic ablation of mKitL in thymic VECs blocks their c-Kit responsiveness and proliferation during neonatal thymic expansion. Therefore, mKitL–c-Kit form a bi-directional signaling complex that acts in the developing thymus to coordinate thymic VEC and early thymic progenitor (ETP) expansion by simultaneously promoting ETP survival and VEC proliferation. This mechanism may be relevant to both normal tissues and malignant tumors that depend on KitL–c-Kit signaling for their proliferation.

2018-11-21 | PXD011061 | Pride

Gene expression analysis of hematopoetic progenitors

Project description:Bivalency has been postulated to be a ‘poised’ state from which removal of one or the other mark permits gene activation or repression. To determine whether gene expression changes accompanied resolution of bivalent genes, we first obtained the expression pattern of hematopoietic stem cells (HSC), lymphoid-primed multipotent progenitors (LMPP), common lymphoid progenitors (CLP) , early thymic precursors (ETP), double negative 2 (DN2) and double negative 3 (DN3) cells using Affymetrix arrays. Consistent with trends noted in earlier studies, K4+ genes were, on average, expressed at higher levels compared to K4+K27+ or K27+ genes in all subsets.

2018-12-31 | GSE43427 | GEO

The Expansion of Thymopoiesis in Neonatal Mice is Dependent on Expression of High mobility group A 2 protein (Hmga2)

Project description:The most immature progenitors in the murine thymus are early T lineage progenitors (ETP). These cells are the precursors of more mature thymocytes that ultimately leave the thymus and colonize peripheral lymphoid tissues. As part of our efforts to define age-related changes in ETP, we harvested them from mice of different ages and performed whole transcriptome profiling. This analysis revealed major differences in patterns of gene expression between young and old ETP, and we were particularly struck by the significantly reduced expression of the gene encoding high mobility group A 2 protein (Hmga2).

2016-03-19 | GSE67112 | GEO

Role of barhl1 in amphbian cerebellum

Project description:Cerebellar granule neuron progenitors (GNPs) originate from the upper rhombic lip (URL), a germinative niche in which developmental defects produce human diseases. T-cell factor (TCF) responsiveness and Notch dependence are hallmarks of self-renewal in neural stem cells. TCF activity, together with transcripts encoding proneural gene repressors hairy and enhancer of split (Hes/Hey), are detected in the URL; however, their functions and regulatory modes are undeciphered. Here, we established amphibian as a pertinent model for studying vertebrate URL development. The amphibian long-lived URL is TCF active, whereas the external granular layer (EGL) is non-proliferative and expresses hes4 and hes5 genes. Using functional and transcriptomic approaches, we show that TCF activity is necessary for URL emergence and maintenance. We establish that the transcription factor Barhl1 controls GNP exit from the URL, acting partly through direct TCF inhibition. Identification of Barhl1 target genes suggests that, besides TCF, Barhl1 inhibits transcription of hes5 genes independently of Notch signaling. Observations in amniotes suggest a conserved role for Barhl in maintenance of the URL and/or EGL via co-regulation of TCF, Hes and Hey genes.

2024-09-11 | GSE276791 | GEO

Asynchronous combinatorial action of four regulatory factors activates Bcl11b for T cell commitment

Project description:During T cell development, multipotent progenitors relinquish competence for other fates and commit to the T cell lineage by turning on Bcl11b, which encodes a transcription factor. To clarify lineage commitment mechanisms, we followed developing T cells at the single-cell level using Bcl11b knock-in fluorescent reporter mice. Notch signaling and Notch activated transcription factors collaborate to activate Bcl11b expression irrespectively of Notch-dependent proliferation. These inputs work via three distinct, asynchronous mechanisms: an early locus âpoisingâ function dependent on TCF-1 and GATA-3, a stochastic-permissivity function dependent on Notch signaling, and a separate amplitude-control function dependent on Runx1, a factor already present in multipotent progenitors. Despite their necessity for Bcl11b activation, these inputs act in a stage specific manner, providing a multitiered mechanism for developmental gene regulation. Two sets of samples were generated from DN T-cell sub-populations derived from culture of bone marrow progenitors from mice containing a knock-in Bcl11b-YFP reporter

2016-06-27 | E-GEOD-76606 | biostudies-arrayexpress

Complete hematologic response of early-T-cell progenitor acute lymphoblastic leukemia to the gamma-secretase inhibitor BMS-906024: genetic and epigenetic findings in an outlier case

Project description:Notch pathway antagonists such as gamma-secretase inhibitors (GSI) are being tested in diverse cancers, but exceptional responses have yet to be reported. We describe the case of a patient with relapsed/refractory early-T-cell progenitor acute lymphoblastic leukemia (ETP-ALL) who achieved a complete hematologic response following treatment with the GSI BMS-906024. Whole exome sequencing of leukemic blasts revealed heterozygous gain-of-function driver mutations in NOTCH1, CSF3R, and PTPN11, and a homozygous/hemizygous loss-of-function mutation in DNMT3A. The three gain-of-function mutations were absent from remission marrow cells, but the DNMT3A mutation persisted in heterozygous form in remission marrow, consistent with an origin for the patient’s ETP-ALL from clonal hematopoiesis. Ex vivo culture of ETP-ALL blasts confirmed high levels of activated NOTCH1 that were repressed by GSI treatment, and RNA-Seq documented that GSI downregulated multiple known Notch target genes. Surprisingly, one potential target gene that was unaffected by GSI was MYC, a key Notch target in GSI-sensitive T-ALL of cortical T cell type. H3K27ac superenhancer landscapes near MYC showed a pattern previously reported in acute myeloid leukemia (AML) that is sensitive to BRD4 inhibitors, and in line with this ETP-ALL blasts downregulated MYC in response to the BRD4 inhibitor JQ1. To our knowledge, this is the first example of complete response of a Notch-mutated ETP-ALL to a Notch antagonist and is also the first description of chromatin landscapes associated with ETP-ALL. Our experience suggests that additional attempts to target Notch in Notch-mutated ETP-ALL are merited. RNAseq and H3K27Ac ChIP seq of primary leukemic blasts treated in vitro with vehicle control or gamma-secretase inhibitor BMS-096024

2015-07-29 | E-GEOD-71414 | biostudies-arrayexpress

Complete hematologic response of early-T-cell progenitor acute lymphoblastic leukemia to the gamma-secretase inhibitor BMS-906024: genetic and epigenetic findings in an outlier case

2015-07-29 | GSE71414 | GEO

Intriniscally disordered domain of transcription factor TCF-1 is requried for T cell developmental fidelity [RNA-Seq]

Project description:The transcription factor TCF-1 has long been demonstrated to be essential for normal T cell development, with a critical role at the earliest stages of lineage specification downstream of Notch signaling in the thymus. Recent work has shown that TCF-1 targets and is essential for the opening of chromatin in T cells to orchestrate the gene regulatory cascade that occurs during development. However, besides the high mobility group DNA binding domain, no portion of the TCF-1 protein has been characterized to determine its role in hematopoiesis. In this study, we fully characterize all regions of TCF-1 and assess their importance in TCF-1-driven epigenetic and transcriptional regulation as well as in endowing developmental competency to the T cell lineage. Surprisingly, we identified an intrinsically disordered N-terminal region of TCF-1 termed “L1” that is necessary for efficient transition from early thymic progenitors to double-negative (DN)2 T cells. The few T cells that develop from progenitor cells expressing mutant TCF-1 lacking the L1 region exhibit lineage infidelity that was distinct and unique from the lineage diversion of TCF-1-deficient cells. Transcriptional and epigenetic profiling indicated that the L1 region was required for efficient target gene transactivation which correlated with the de-repression of a set of Gata2-driven genes normally restricted to the mast cell and dendritic cell lineages. DL1 mutant DN2 cells showed aberrant opening of previously silent chromatin at mast cell genes and Gata2-bound enhancers. These data support an essential role for TCF-1’s intrinsically disordered N-terminus in maintaining fidelity to the T cell lineage through carefully balanced activation of partner transcription factors that are required to repress alternative lineages.

2023-07-06 | GSE213236 | GEO

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