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Nuclear Vav3 is required for canonical PRC1 activity in B-cell lymphoblastic leukemogenesis

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE196378 | GEO | 2022/04/16

REPOSITORIES: GEO

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Nuclear Vav3 is required for canonical PRC1 activity in B-cell lymphoblastic leukemogenesis (CUT&RUN)

Project description:Acute B-cell lymphoblastic leukemia (B-ALL) represents a multiclonal evolution of B-cell progenitors endowed with both tumor-initiating and propagating properties. We have previously shown that the concurrent overexpression and activation of both the Rac guanine nucleotide exchange factor (RacGEF) Vav3 and Rac GTPases is required for BCR-ABL-mediated leukemogenesis. Here, we show that upon BCR-ABL expression, Vav3 expression becomes predominantly nuclear. In this location, Vav2 interacts with BCR-ABL, Rac, and the canonical polycomb repression complex proteins Bmi1, Ring1b and Ezh2. The GEF activity of Vav3 is required for B-cell proliferation and Bmi1-dependent B-cell progenitor self-renewal, nuclear Rac activation, protein interaction with Bmi1, H2A(K119) mono-ubiquitination (H2AK119Ub), and repression of downstream target loci. Vav3 deficiency results in de-repression and repression of loci encoding negative regulators of cell proliferation and oncogenic transcriptional factors, respectively. Mechanistically, we show that Vav3 prevents the Phlpp2-sensitive and Akt (S473)-dependent phosphorylation of Bmi1 on the regulatory residue S314 that, in turn, promotes the transcriptional factor reprogramming of leukemic B-cell progenitors. These results highlight the importance of non-canonical nuclear Rho GTPase signaling in leukemogenesis.

2022-04-16 | GSE196375 | GEO

Nuclear Vav3 is required for canonical PRC1 activity in B-cell lymphoblastic leukemogenesis (RNA-Seq)

2022-04-16 | GSE196377 | GEO

Nuclear Vav3 is required for canonical PRC1 activity in B-cell lymphoblastic leukemogenesis

Project description:Nuclear Vav3 is required for canonical PRC1 activity in B-cell lymphoblastic leukemogenesis

| PRJNA804538 | ENA

Nuclear Vav3 is required for canonical PRC1 activity in B-cell lymphoblastic leukemogenesis (CUT&RUN)

Project description:Nuclear Vav3 is required for canonical PRC1 activity in B-cell lymphoblastic leukemogenesis (CUT&RUN)

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Nuclear Vav3 is required for canonical PRC1 activity in B-cell lymphoblastic leukemogenesis (RNA-Seq)

Project description:Nuclear Vav3 is required for canonical PRC1 activity in B-cell lymphoblastic leukemogenesis (RNA-Seq)

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A central role for canonical PRC1 in shaping the 3D nuclear landscape.

Project description:Polycomb group (PcG) proteins silence gene expression by chemically and physically modifying chromatin. A subset of PcG target loci are compacted and cluster in the nucleus; a conformation that is thought to contribute to gene silencing. However, how these interactions influence gross nuclear organization and their relationship with transcription remains poorly understood. Here we examine the role of Polycomb-repressive complex 1 (PRC1) in shaping 3D genome organization in mouse embryonic stem cells (mESCs). Using a combination of imaging and Hi-C analyses, we show that PRC1-mediated long-range interactions are independent of CTCF and can bridge sites at a megabase scale. Impairment of PRC1 enzymatic activity does not directly disrupt these interactions. We demonstrate that PcG targets coalesce in vivo, and that developmentally induced expression of one of the target loci disrupts this spatial arrangement. Finally, we show that transcriptional activation and the loss of PRC1-mediated interactions are separable events. These findings provide important insights into the function of PRC1, while highlighting the complexity of this regulatory system.

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Maintenance of Leukemic Cell Identity by the Activity of the Polycomb Complex PRC1

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2016-10-21 | E-GEOD-67552 | biostudies-arrayexpress

Non-Canonical PRC1.1 is required for the activity of Menin-MLL1 Inhibitors in NUP98-Rearranged AML

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

2024-09-16 | GSE249218 | GEO

Nuclear Receptor Corepressors are Required for the Histone Deacetylase Activity of HDAC3 In Vivo

Project description:Histone deacetylase 3 (HDAC3) is an epigenome-modifying enzyme that is required for normal mouse development and tissue-specific functions. In vitro, HDAC3 protein itself has minimal enzyme activity, but gains its histone deacetylation function from stable association with the conserved deacetylase activation domain (DAD) contained in nuclear receptor corepressors NCOR1 and SMRT. Here we show that HDAC3 enzyme activity is undetectable in mice bearing point mutations in the DAD of both NCOR1 and SMRT (NS-DADm), despite normal levels of HDAC3 protein. Local histone acetylation is increased, and genomic HDAC3 recruitment is reduced though not abrogated. Remarkably, the NS-DADm mice are born and live to adulthood, whereas genetic deletion of HDAC3 is embryonic lethal. These findings demonstrate that nuclear receptor corepressors are required for HDAC3 enzyme activity in vivo, and suggest that a deacetylase-independent function of HDAC3 may be required for life. This SuperSeries is composed of the SubSeries listed below. Refer to individual Series.

2013-01-01 | E-GEOD-42541 | biostudies-arrayexpress

PRC1 catalytic activity is central to Polycomb system function.

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

2020-01-08 | GSE132754 | GEO