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The ubiquitin ligase HUWE1 regulates hematopoietic stem cell maintenance and lymphoid commitment [microarray]

ABSTRACT: We identified the ubiquitin ligase Huwe1 as a crucial regulator of hematopoietic stem cell (HSC) functions. We generated Huwe1 conditional knock-out mice and discovered that the loss of this ligase causes an increased proliferation and stem cell exhaustion, together with a decreased lymphoid specification in vivo. We observed that the ubiquitin ligase Huwe1 is controlling the expression of N-myc at the level of the most immature stem and progenitor hematopoietic populations, mediating the described effects.

ORGANISM(S): Mus musculus

PROVIDER: GSE85832 | GEO | 2016/08/20

SECONDARY ACCESSION(S): PRJNA339594

REPOSITORIES: GEO

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The ubiquitin ligase HUWE1 regulates hematopoietic stem cell maintenance and lymphoid commitment [microarray]

Project description:We identified the ubiquitin ligase Huwe1 as a crucial regulator of hematopoietic stem cell (HSC) functions. We generated Huwe1 conditional knock-out mice and discovered that the loss of this ligase causes an increased proliferation and stem cell exhaustion, together with a decreased lymphoid specification in vivo. We observed that the ubiquitin ligase Huwe1 is controlling the expression of N-myc at the level of the most immature stem and progenitor hematopoietic populations, mediating the described effects. Hematopoietic stem cells (HSC) from the bone marrow of transgenic animals carrying a N-myc/mCherry fusion gene were sorted according to N-myc expression (defined by mCherry) into N-myc high and low subpopulations. Each of these 2 populations was subjected to microarray gene expression profiling.

2016-08-20 | E-GEOD-85832 | biostudies-arrayexpress

The ubiquitin ligase HUWE1 regulates hematopoietic stem cell maintenance and lymphoid commitment [high-throughput sequencing]

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The ubiquitin ligase HUWE1 regulates hematopoietic stem cell maintenance and lymphoid commitment

Project description:The ubiquitin ligase HUWE1 regulates hematopoietic stem cell maintenance and lymphoid commitment

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Regulation of stem cell maintenance and lymphoid specification by the ubiquitin ligase Huwe1

Project description:The ubiquitin ligase Huwe1 regulates stem cell quiescence, maintenance and lymphoid specification by controlling the expression of N-Myc.

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Tumor cell-specific inhibition of MYC function using small molecule inhibitors of the HUWE1 ubiquitin ligase

Project description:Deregulated expression of MYC is a driver of colorectal carcinogenesis, necessitating novel strategies to inhibit MYC function. The ubiquitin ligase HUWE1 (HECTH9, ARFBP1, MULE) associates with both MYC and the MYC-associated protein MIZ1. We show here that HUWE1 is required for growth of colorectal cancer cells in culture and in orthotopic xenograft models. Using high throughput screening, we identify small molecule inhibitors of HUWE1, which inhibit MYC-dependent transactivation in colorectal cancer cells, but not in stem and normal colon epithelial cells. Inhibition of HUWE1 stabilizes MIZ1. MIZ1 globally accumulates on MYC target genes and contributes to repression of MYC-activated target genes upon HUWE1 inhibition. Our data show that transcriptional activation by MYC in colon cancer cells requires the continuous degradation of MIZ1 and identify a novel principle that allows for inhibition of MYC function in tumor cells. MIZ1 and MYC ChIPseq experiments in HUWE1 inhibitor-treated Ls174T cells as well as RNAseq experiments in HUWE1- or MIZ1-depleted Ls174T cells after HUWE1 inhibitor treatment. Sequencing was performed on an Illumina Genome Analyzer IIx.

2014-10-21 | E-GEOD-59223 | biostudies-arrayexpress

Tumor cell-specific inhibition of MYC function using small molecule inhibitors of the HUWE1 ubiquitin ligase

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Regulation of the cardiac transcriptome by the E3 ubiquitin ligase Huwe1.

Project description:Analysis of the cardiac transcriptome by heart-specific acute genetic ablation of Huwe1 in adult male mice employing a tamoxifen-inducible Cre-loxP system.

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The ubiquitin ligase Huwe1 regulates the maintenance and lymphoid commitment of hematopoietic stem cells.

Project description:Hematopoietic stem cells (HSCs) are dormant in the bone marrow and can be activated in response to diverse stresses to replenish all blood cell types. We identified the ubiquitin ligase Huwe1 as a crucial regulator of HSC function via its post-translational control of the oncoprotein N-myc (encoded by Mycn). We found Huwe1 to be essential for HSC self-renewal, quiescence and lymphoid-fate specification in mice. Through the use of a fluorescent fusion allele (MycnM), we observed that N-myc expression was restricted to the most immature, multipotent stem and progenitor populations. N-myc expression was upregulated in response to stress or following loss of Huwe1, which led to increased proliferation and stem-cell exhaustion. Mycn depletion reversed most of these phenotypes in vivo, which suggested that the attenuation of N-myc by Huwe1 is essential for reestablishing homeostasis following stress.

| S-EPMC5117833 | biostudies-literature

The ubiquitin ligase HUWE1 regulates hematopoietic stem cell maintenance and lymphoid commitment

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

2016-08-20 | E-GEOD-85833 | biostudies-arrayexpress

Tumor cell-specific inhibition of MYC function using small molecule inhibitors of the HUWE1 ubiquitin ligase

Project description:HUWE1 was depleted in Ls174T cells with an shRNA and the expression changes relative to a control shRNA were analyzed with microarray. Ls174T cells were treated with two separate HUWE1 inhibitor compounds (BI8622/BI8626) at concentrations of 20 uM and expression profiles relative to DMSO treated control were monitored via microarray. HUWE1-depleted Ls174T cells were treated with BI8622 (20uM) and expression profiles relative to BI8622-treated non-depleted cells were analyzed.

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