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A double negative thymocyte specific enhancer augments Notch1 signaling to direct early T cell progenitor expansion, lineage restriction and -selection.

ABSTRACT: A double negative thymocyte specific enhancer augments Notch1 signaling to direct early T cell progenitor expansion, lineage restriction and -selection.

PROVIDER: PRJNA775992 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR16612721.fastq.gz	Fastqsanger.gz
	SRR16612722.fastq.gz	Fastqsanger.gz
	SRR16612723.fastq.gz	Fastqsanger.gz

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Similar Datasets

A double negative thymocyte specific enhancer augments Notch1 signaling to direct early T cell progenitor expansion, lineage restriction and -selection.

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.

2022-09-01 | GSE186764 | GEO

A double negative thymocyte specific enhancer augments Notch1 signaling to direct early T cell progenitor expansion, lineage restriction and b-selection.

Project description:T-cell differentiation requires Notch1 signaling. Here we show that an enhancer upstream of Notch1 active in double-negative (DN) 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-lineage commitment and TCR V-DJ recombination, Cd3 expression and -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.

2022-09-01 | GSE211079 | GEO

A double negative thymocyte specific enhancer augments Notch1 signaling to direct early T cell progenitor expansion, lineage restriction and b-selection.

Project description:A double negative thymocyte specific enhancer augments Notch1 signaling to direct early T cell progenitor expansion, lineage restriction and b-selection.

| PRJNA869100 | ENA

A double-negative thymocyte-specific enhancer augments Notch1 signaling to direct early T cell progenitor expansion, lineage restriction and β-selection.

Project description:T cell differentiation requires Notch1 signaling. In the present study, we show that an enhancer upstream of Notch1 active in double-negative (DN) mouse thymocytes is responsible for raising Notch1 signaling intrathymically. This enhancer is required to expand multipotent progenitors intrathymically while delaying early differentiation until lineage restrictions have been established. Early thymic progenitors lacking the enhancer show accelerated differentiation through the DN stages and increased frequency of B, innate lymphoid (IL) and natural killer (NK) cell differentiation. Transcription regulators for T cell lineage restriction and commitment are expressed normally, but IL and NK cell gene expression persists after T cell lineage commitment and T cell receptor β VDJ recombination, Cd3 expression and β-selection have been 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.

| S-EPMC10187983 | biostudies-literature

Thymocyte Negative Selection

Project description:Fetal thymic organ culture (FTOC) DC2.5 CD4+CD8+ thymocytes from B6g7 or NOD background. 0 or 16 hour after addition of the BDC mimitope Keywords = BDC2.5 FTOC thymocyte Keywords: dose response

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Cholinergic regulation of thymocyte negative selection

Project description:Cholinergic regulation of thymocyte negative selection

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Notch-Induced Endoplasmic Reticulum-Associated Degradation Governs Thymocyte β Selection

Project description:β -selection imposes a considerable demand for new protein synthesis of the newly rearranged Tcrβ gene and the multiple factors that execute the transcriptional and metabolic programs demanded by DN thymocyte proliferation. However, how proteome homeostasis or “proteostasis” is regulated during thymocyte development is largely unknown. Here, we show that the endoplasmic reticulum (ER)- associated degradation (ERAD), but not the unfolded protein response (UPR), is the master regulator of physiological ER proteostasis in immature DN thymocytes. The ERAD machinery was critically required for successful β-selection of DN3 thymocytes and consequently, ERAD deficiency impeded αβ T cell development. The Sel1L-Hrd1 complex is the most conserved branch of mammalian ERAD machinery. Deletion of Sel1l impaired DN3 to DN4 thymocyte transition and severely impaired αβ T cell development. Mechanistically, Sel1l deficiency induced unresolved ER stress that triggered thymocyte apoptosis through the PERK pathway. This study revealed the stringent protein quality control through the SEL1L-ERAD pathway is required for successful b-selection and the development of the ab T cells that mediate adaptive immunity.

2021-05-07 | GSE173993 | GEO

RNA-seq data from double positive thymocyte and CD4 or CD8 single positive spleen T cell

Project description:Control RNA-seq data for thymocyte and spleen T cell.

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NOTCH1 gene amplification promotes expansion of Cancer Associated Fibroblast populations in human skin

Project description:Cancer associated fibroblasts (CAFs) represent a key component of the tumor microenvironment. Possible genomic alterations in these cells remain a point of contention. The skin is constantly exposed to clastogenic insults, such as UVA light that can target directly the stromal compartment, therefore representing a relevant model to study. Here we report that CAFs from skin Squamous Cell Carcinoma (SCC) lesions display chromosomal alterations, with heterogeneous levels of NOTCH1 gene amplification that also occur, to a lesser extent, in dermal fibroblasts of apparently unaffected skin. The fraction of the latter cells harboring NOTCH1 gene amplification is expanded by chronic UVA exposure, which induces a DNA damage response (DDR) to which CAFs are resistant. The selective advantage conferred by NOTCH1 gene amplification and over-expression can be explained by NOTCH1 ability to block DDR-mediated growth arrest through competitive suppression of ATM-FOXO3a association and downstream signaling cascade. These findings are of translational significance as, in an orthotopic model of skin SCC, genetic or pharmacological inhibition of NOTCH1 activity suppresses cancer / stromal cells expansion. Thus, NOTCH1 amplification and increased expression contribute to CAFs evolution and are an attractive target for preventing cancer / stromal cell expansion.

2020-08-25 | GSE113577 | GEO

Non-overlapping functions for Notch1 and Notch3 during murine steady state thymic lymphopoiesis.

Project description:Notch1 signaling is absolutely essential for steady-state thymic lymphopoiesis, but the role of other Notch receptors, and their potential overlap with the function of Notch1, remains unclear. Here we show that like Notch1, Notch3 is differentially expressed by progenitor thymocytes, peaking at the DN3 progenitor stage. Using mice carrying a gene-trapped allele, we show that thymic cellularity is slightly reduced in the absence of Notch3, although progression through the defined sequence of TCR-αβ development is normal, as are NKT and TCRγδ cell production. The absence of a profound effect from Notch3 deletion is not explained by residual function of the gene-trapped allele, since insertion mapping suggests that the targeted allele would not encode functional signaling domains. We also show that although Notch1 and Notch3 are co-expressed on some early intrathymic progenitors, the relatively mild phenotype seen after Notch3 deletion does not result from the compensatory function of Notch1, nor does Notch3 function explain the likewise mild phenotype seen after conditional (intrathymic) deletion of Notch1. Our studies indicate that Notch1 and Notch3 carry out non-overlapping functions during thymocyte differentiation, and that while Notch1 is absolutely required early in the lymphopoietic process, neither receptor is essential at later stages.

2011-08-03 | GSE30631 | GEO

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