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Gene Expression Analysis of WT and dnTCF4-expressing Short-Term Hematopoietic Stem Cells (ST-HSC)

ABSTRACT: The canonical Wnt signaling pathway is mediated by interaction of b-catenin with the TCF/LEF transcription factors and subsequent transcriptional activation of Wnt-target genes. In the hematopoietic system, the function of the pathway has been mainly investigated by genetic manipulation of b-catenin. However, this approach does not allow to discriminate between TCF/LEF dependent or independent b-catenin activity. Here, we employed a transgenic mouse model expressing a truncated dominant negative form of the human TCF4 transcription factor (dnTCF4) which abrogates activation of Wnt target genes even when b-catenin is stabilized and translocated into the nucleus while preserving its TCF/LEF independent activities. The disruption of the b-catenin-TCF/LEF interaction results in reduced granulocytic differentiation accompanied with an accumulation of short-term hematopoietic stem cells (ST-HSC) and granulocytic progenitors. In order to investigate the mechanism responsible for the insufficient production of granulocytes, we performed a transcriptomic analysis of ST-HSC from dnTCF4-expressing and control WT mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE139668 | GEO | 2020/08/25

REPOSITORIES: GEO

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TCF/LEF dependent and independent regulation of Wnt/beta-catenin transcription

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TCF/LEF dependent and independent regulation of Wnt/beta-catenin transcription

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Multiple regulatory intrinsically disordered motifs control FOXO4 transcription factor binding and function

Project description:Transcription factors harbour defined intrinsically disordered regulatory regions, which raises the question of how they mediate binding to structured co-regulators and how this regulates activity. Here, we present a detailed molecular regulatory mechanism of Forkhead box O4 (FOXO4) by the structured transcriptional co-regulator β-catenin. We find that the largely disordered FOXO4 C-terminal region, which contains its transactivation domain binds β-catenin through two defined interaction sites, and this is regulated by combined PKB/AKT- and CK1-mediated phosphorylation. Binding of β-catenin competes with the auto-inhibitory interaction of the FOXO4 disordered region with its DNA-binding forkhead domain, and thereby enhances FOXO4 transcriptional activity. Furthermore, we show that binding of the β-catenin inhibitor protein ICAT is compatible with FOXO4 binding to β-catenin, suggesting that ICAT acts as a molecular switch between anti-proliferative FOXO and pro-proliferative Wnt/TCF/LEF signalling. Together these data illustrate how the interplay of intrinsically disordered regions, post-translational modifications and co-factor binding contribute to transcription factor function. Highlights • The interaction network between FOXO4 and β-catenin was deciphered • FOXO4 auto-inhibition interferes with DNA binding and is counter-acted by β-catenin • FOXO4 exists in multiple conformations regulated by phosphorylation and co-factors • ICAT switches between FOXO4 and TCF/LEF transcription factors

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Project description:The forkhead box transcription factor FOXQ1 is aberrantly induced in various cancers, and contributes to tumour growth and metastasis. It has been suggested that the oncogenic potential of FOXQ1 may be explained by its activation of the Wnt/β-catenin signalling pathway.However, the mode of action of FOXQ1 in the Wnt pathway remains to be resolved. Here we report that FOXQ1 is bimodal transcriptional activator of Wnt target gene expression in normal and cancer cells. Using co-immunoprecipitation, proximity proteomics, and reporter assays, we show that FOXQ1 engages the Wnt transcriptional complex to promote gene expressionvia TCF/LEF transcription factors.

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2016-02-23 | E-GEOD-78159 | biostudies-arrayexpress

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2016-02-23 | GSE78159 | GEO

Non-coding RNAs Activated in Hepatoblastoma

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