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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE106683 | GEO | 2018/09/21

REPOSITORIES: GEO

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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.

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

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

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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

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The PIAS-like coactivator Zmiz1 directly and selectively coregulates Notch1 in T-cell development and leukemia [ChIP-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. In order to determine whether this interaction occured at chromatin, we performed ChIP-Seq. We identified significant overlap between ICN1, Rbpj, and Zmiz1 peaks. 75% of overlapping ICN1/Rbpj peaks overlapped with Zmiz1 (HA) peaks (273 peaks). The size of Zmiz1 (HA) peaks had moderate correlation with the size of Rbpj and ICN1 peaks. Like Rbpj and ICN1 peaks, Zmiz1 (HA) peaks were associated with activating H3K27ac, H3K4me1, and H3K4me3 chromatin marks and were devoid of repressive H3K27me3 marks. These data suggest that Zmiz1 is a selective Notch regulator. It co-binds only a subset of ICN1 and Rbpj-regulated sites.

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