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The Zmiz1-Notch1 interaction induces Myc expression to drive steady state and stress thymopoiesis [DN3]

ABSTRACT: The Zmiz1-Notch1 interaction induces Myc expression to drive steady state and stress thymopoiesis [DN3]

PROVIDER: PRJNA417671 | ENA |

REPOSITORIES: ENA

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The Zmiz1-Notch1 interaction induces Myc expression to drive steady state and stress thymopoiesis [DN3]

Project description:Notch1 signaling ramps up to very high levels in order to drive CD4-CD8- double-negative (DN) thymocytes to the CD4+CD8+ double-positive (DP) stage. During this important phase of T-cell development, which is known as the DN-DP transition, it is unclear whether the Notch1 complex simply strengthens its signal output as an isolated unit or recruits cofactors to amplify its signals. We previously showed that the PIAS-like coactivator Zmiz1 is a direct and context-dependent cofactor of Notch1 in T-cell leukemia. Using conditional knockout mouse models, we show that like inactivation of Notch, inactivation of Zmiz1 impaired the DN-DP transition under steady state and stress conditions. To determine mechanism, we performed RNA-Seq on sorted DN3 cells that were deprived of Zmiz1 signals either acutely (DeltaTamCre) or chronically (DeltaMxCre). To differentiate Notch1-independent from Notch1-dependent target genes, we also performed RNA-Seq on DN3 cells that were deprived of Notch1 signals using the anti-NRR Notch1 antibody. Our data suggests that Zmiz1 selectively amplifies a subset of Notch1 target genes in DN3 cells, such as Myc.

2018-09-21 | GSE106683 | GEO

The Zmiz1-Notch1 interaction induces Myc expression to drive steady state and stress thymopoiesis [ETP and DN3]

Project description:Notch1 signaling ramps up to very high levels in order to drive CD4-CD8- double-negative (DN) thymocytes to the CD4+CD8+ double-positive (DP) stage. During this important phase of T-cell development, which is known as the DN-DP transition, it is unclear whether the Notch1 complex simply strengthens its signal output as an isolated unit or recruits cofactors to amplify its signals. We previously showed that the PIAS-like coactivator Zmiz1 is a direct and context-dependent cofactor of Notch1 in T-cell leukemia. Using conditional knockout mouse models, we show that like inactivation of Notch, inactivation of Zmiz1 impaired the DN-DP transition under steady state and stress conditions. To determine mechanism, we performed RNA-Seq on sorted early T-lineage progenitor (ETP) and DN3 cells that were deprived of Zmiz1 signals either acutely (DeltaTamCre) or chronically (DeltaMxCre). To differentiate Notch1-independent from Notch1-dependent target genes, we also performed RNA-Seq on ETP and DN3 cells that were deprived of Notch1 signals using the anti-NRR Notch1 antibody. Our data suggests that Zmiz1 selectively amplifies a subset of Notch1 target genes in DN3 cells, such as Myc. In contrast, Zmiz1 does not have these functions in ETP cells, thus indicating stage-specific roles of Zmiz1.

2018-09-21 | GSE116120 | GEO

The Zmiz1-Notch1 interaction induces Myc expression to drive steady state and stress thymopoiesis [ETP and DN3]

Project description:The Zmiz1-Notch1 interaction induces Myc expression to drive steady state and stress thymopoiesis [ETP and DN3]

| PRJNA477331 | ENA

The Zmiz1-Notch1 interaction induces Myc expression to drive steady state and stress thymopoiesis

Project description:The Zmiz1-Notch1 interaction induces Myc expression to drive steady state and stress thymopoiesis

| PRJNA477341 | ENA

Identification of the molecular targets of miR-185 in DN3 stage thymocytes

Project description:T cell-specific overexpression of miR-185 caused a developmental block at DN3 stage of thymopoiesis. DN3 stage thymocytes were sorted from the wild type (C57BL/6) and miR-185 Tg mice, followed by total RNA isolation.

2013-10-28 | E-GEOD-49057 | biostudies-arrayexpress

Identification of the molecular targets of miR-185 in DN3 stage thymocytes

Project description:T cell-specific overexpression of miR-185 caused a developmental block at DN3 stage of thymopoiesis.

2013-10-28 | GSE49057 | 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

The PIAS-like coactivator Zmiz1 directly and selectively coregulates Notch1 in T-cell development and leukemia [RNA-Seq]

Project description:The most recurrently mutated oncogene in T-cell acute lymphoblastic leukemia (T-ALL) is NOTCH1. The core Notch complex consists of an ICN protein, a Maml cofactor, and the DNA binding factor Rbpj. The known direct cofactors of Notch appear to act nonselectively, homogeneously driving Notch gene expression functions. It is unclear whether there are direct cofactors of Notch that act selectively and heterogeneously regulate ICN. We discovered that Zmiz1, a Protein Inhibitor of Activated STAT (PIAS)-like coactivator, directly bound ICN1. ChIP-Seq showed that Zmiz1 selectively co-bound only a subset of Notch-regulated enhancers. This led to hypothesize that Zmiz1 regulates only a subset of Notch1 target genes. To investigate this, we performed RNA-Seq on four 8946 cell linesin which L1601P (activated Notch1) or Zmiz1 were expressed alone or in combination. Zmiz1 induced ~10% of Notch target genes. The Notch target gene that was most strongly induced by Zmiz1 was Myc. Our data suggest that Zmiz1 selectively amplifies a subset of Notch target genes with strong amplification of Myc. RNA-Seq in a murine T-ALL cell line

2015-10-28 | E-GEOD-66145 | biostudies-arrayexpress

The PIAS-like coactivator Zmiz1 directly and selectively coregulates Notch1 in T-cell development and leukemia [RNA-Seq]

2015-10-28 | GSE66145 | GEO

The Zmiz1-Notch1 interaction induces Myc expression to drive steady state and stress thymopoiesis

Project description:This SuperSeries is composed of the SubSeries listed below.

2018-09-21 | GSE116125 | GEO