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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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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. 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.

ORGANISM(S): Mus musculus

SUBMITTER: Bryan King

PROVIDER: E-GEOD-85832 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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.

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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.

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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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Hematopoietic Stem Cell Differentiation Regulated by a Single Ubiquitin Ligase: Substrate Complex

Project description:Hematopoietic stem cell (HSC) differentiation is regulated by cell-intrinsic and extrinsic cues. In addition to transcriptional regulation, post-translational regulation may also control HSC differentiation. To test this hypothesis, we visualized ubiquitin-regulated protein stability of a single transcription factor, c-Myc. The stability of c-Myc protein was instructive of HSC quiescence and c-Myc protein abundance was controlled by the ubiquitin ligase Fbw7. Fine changes in stability of c-Myc protein regulated the HSC “gene expression signature”. Using whole genome genomic approaches, we identified specific regulators of HSC function that are directly controlled by c-Myc binding, however adult HSCs and embryonic stem cells sense and interpret distinctly c-Myc regulated gene expression. These studies show a ubiquitin ligase–substrate pair can orchestrate the molecular program of HSC differentiation.

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Hematopoietic Stem Cell Differentiation Regulated by a Single Ubiquitin Ligase: Substrate Complex

Project description:Hematopoietic stem cell (HSC) differentiation is regulated by cell-intrinsic and extrinsic cues. In addition to transcriptional regulation, post-translational regulation may also control HSC differentiation. To test this hypothesis, we visualized ubiquitin-regulated protein stability of a single transcription factor, c-Myc. The stability of c-Myc protein was instructive of HSC quiescence and c-Myc protein abundance was controlled by the ubiquitin ligase Fbw7. Fine changes in stability of c-Myc protein regulated the HSC âgene expression signatureâ. Using whole genome genomic approaches, we identified specific regulators of HSC function that are directly controlled by c-Myc binding, however adult HSCs and embryonic stem cells sense and interpret distinctly c-Myc regulated gene expression. These studies show a ubiquitin ligaseâsubstrate pair can orchestrate the molecular program of HSC differentiation. Gene expression profiles from c-Myc-High and c-Myc-Low expressing Lineage negative, c-Kit and Sca1 positive (LSKs) were compared using genome wide mRNA expression profiling by Affymetrix genechip arrays (Mouse 430 2.0) and key targets were validated by chromatin immunoprecipitation experiments.

2010-03-07 | E-GEOD-19502 | biostudies-arrayexpress

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

2014-10-21 | GSE59223 | GEO

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

| PRJNA339518 | ENA

Mus musculus

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

| PRJNA339594 | ENA

Transcription profiling of mouse Fbw7-/-/hematopoietic stem cells

Project description:Ubiquitination is a post-translational mechanism of control of diverse cellular processes. We focus here on the ubiquitin ligase Fbw7, a recently identified hematopoietic tumor suppressor that can target for degradation several important oncogenes including Notch1, c-Myc and cyclin E. We have generated conditional Fbw7 knock-out animals and inactivated the gene in hematopoietic stem cells (HSC) and their differentiated progeny. Deletion of Fbw7 specifically and rapidly affects the HSC compartment in a cell-autonomous manner. Fbw7-/- HSCs show defective maintenance of quiescence, leading to impaired self-renewal and a severe loss of competitive repopulating capacity. Furthermore, Fbw7-/- HSC are unable to colonize the thymus leading to a profound depletion of T cell progenitors. Deletion of Fbw7 in bone marrow stem cells and progenitors leads to the stabilization of c-Myc, a transcription factor previously implicated in HSC self-renewal. On the other hand, neither Notch1 nor cyclin E are stabilized in the bone marrow of Fbw7 deficient mice. Genome-wide transcriptome studies of Fbw7-/- HSC and hematopoietic progenitors indicate that Fbw7 controls, through the regulation of HSC cell cycle entry, the global transcriptional âsignatureâ that is associated with the quiescent, self-renewing HSC phenotype. Transcriptional consequences of inactivating Fbw7 in LKS cells. Experiment Overall Design: Four samples were analyzed: wild-type (WT) control and Fbw7-deficient (FBW7) Lin-ckit+Sca1+ (LSK) cells, as well as Lin-ckit+Sca1- myeloid progenitor (MP) cells, which served as a control for LSK-enriched/specific genes. Total bone marrow cells were pooled from three WT and three FBW7 mice before sorting LSK and MP populations.

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