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ChIP-seq and RNA-seq analyses identify Wnt and Fgf signaling pathways as Prep1 targets in mouse embryonic stem cells

ABSTRACT: The Prep1 (Pknox1) homeodomain transcription factor is essential at multiple stages of embryo development. In the E11.5 embryo trunk, we previously estimated that Prep1 binds about 3,300 genomic sites at a highly specific decameric consensus sequence, mainly governing basal cellular functions. We now show that in embryonic stem (ES) cells Prep1 binding pattern only partly overlaps that of the embryo trunk, with about 2,000 novel sites, highlighting a change of targets between embryonic differentiated v. embryonic stem cells. RNA-seq identifies about 1800 genes down-regulated in Prep1- /- ES cells which belong to gene ontology categories not enriched in the E11.5 Prep1i/i differentiated embryo, including in particular the Wnt and Fgf pathways. Indeed, we find aberrant Wnt and Fgf expression levels in the Prep1-/- ES cells which agrees with a deficient embryoid bodies (EBs) differentiation. Re-establishment of the Prep1 level rescues the phenotype.

ORGANISM(S): Mus musculus

PROVIDER: GSE63282 | GEO | 2015/04/01

SECONDARY ACCESSION(S): PRJNA267191

REPOSITORIES: GEO

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ChIP-seq and RNA-seq analyses identify Wnt and Fgf signaling pathways as Prep1 targets in mouse embryonic stem cells

Project description:The Prep1 (Pknox1) homeodomain transcription factor is essential at multiple stages of embryo development. In the E11.5 embryo trunk, we previously estimated that Prep1 binds about 3,300 genomic sites at a highly specific decameric consensus sequence, mainly governing basal cellular functions. We now show that in embryonic stem (ES) cells Prep1 binding pattern only partly overlaps that of the embryo trunk, with about 2,000 novel sites, highlighting a change of targets between embryonic differentiated v. embryonic stem cells. RNA-seq identifies about 1800 genes down-regulated in Prep1- /- ES cells which belong to gene ontology categories not enriched in the E11.5 Prep1i/i differentiated embryo, including in particular the Wnt and Fgf pathways. Indeed, we find aberrant Wnt and Fgf expression levels in the Prep1-/- ES cells which agrees with a deficient embryoid bodies (EBs) differentiation. Re-establishment of the Prep1 level rescues the phenotype. [ChIP-Seq] Examination of genome-wide Prep1 binding in mouse ES cells using ChIP-seq and Illumina GAII sequencing. [RNA-Seq] Examination of gene expression in wild type and Prep1-/- mouse ES cells using RNA-seq and Illumina GAII sequencing.

2015-04-01 | E-GEOD-63282 | biostudies-arrayexpress

Gene expression from Prep1-ablated mice

Project description:The homeodomain transcription factor Prep1 was previously shown to regulate insulin sensitivity. Our aim was to study the specific role of Prep1 for the regulation of energy metabolism in skeletal muscle. Muscle specific ablation of Prep1 resulted in increased expression of respiratory chain subunits. This finding was consistent with an increase in mitochondrial enzyme activity without affecting mitochondrial volume fraction as assessed by electron microscopy. Metabolic phenotyping revealed no differences in daily energy expenditure or body composition. However, during treadmill exercise challenge, Prep1 ablation resulted in a higher maximal oxidative capacity and better endurance. Elevated PGC-1α expression was identified as a cause for increased mitochondrial capacity in Prep1-ablated mice. Prep1 stabilizes p160 Mybbp1a, a known inhibitor of PGC-1α activity. Thereby, P160 protein levels were significantly lower in muscle of Prep1-ablated mice. By a ChIPseq approach, PREP1-binding sites in genes encoding mitochondrial components (e.g. Ndufs2) were identified that might be responsible for elevated OXPHOS proteins in the muscle of Prep1 nullmutants. These results suggest that Prep1 exhibits additional direct effects on regulation of mitochondrial proteins. We therefore conclude that Prep1 is a regulator of oxidative phosphorylation components via direct and indirect mechanisms.

2014-01-01 | GSE52424 | GEO

Gene expression from Prep1-ablated mice

Project description:The homeodomain transcription factor Prep1 was previously shown to regulate insulin sensitivity. Our aim was to study the specific role of Prep1 for the regulation of energy metabolism in skeletal muscle. Muscle specific ablation of Prep1 resulted in increased expression of respiratory chain subunits. This finding was consistent with an increase in mitochondrial enzyme activity without affecting mitochondrial volume fraction as assessed by electron microscopy. Metabolic phenotyping revealed no differences in daily energy expenditure or body composition. However, during treadmill exercise challenge, Prep1 ablation resulted in a higher maximal oxidative capacity and better endurance. Elevated PGC-1Î± expression was identified as a cause for increased mitochondrial capacity in Prep1-ablated mice. Prep1 stabilizes p160 Mybbp1a, a known inhibitor of PGC-1Î± activity. Thereby, P160 protein levels were significantly lower in muscle of Prep1-ablated mice. By a ChIPseq approach, PREP1-binding sites in genes encoding mitochondrial components (e.g. Ndufs2) were identified that might be responsible for elevated OXPHOS proteins in the muscle of Prep1 nullmutants. These results suggest that Prep1 exhibits additional direct effects on regulation of mitochondrial proteins. We therefore conclude that Prep1 is a regulator of oxidative phosphorylation components via direct and indirect mechanisms. Consequence of Prep1 ablation in skeletal muscle was investigated in Prep1deltaSM mice and compared to Prep1 flox mice, both on C57BL/6 background. 4 mice of each genotype were used to extract RNA from the tibialis anterior muscle.

2014-01-01 | E-GEOD-52424 | biostudies-arrayexpress

FGF-WNT omic correlation project

Project description:Both FGF and WNT pathways play important roles in embryonic development, stem cell self-renewal and are frequently deregulated in breast cancer. To study the cooperation between FGF and WNT signaling, we have generated a mouse model, MMTV-WNT1/MMTV-iFGFR1 (WNT/iR1), in which we could chemically overactivate iFGFR1 in a ligand-independent manner.

2017-11-22 | MSV000081730 | MassIVE

Prep1 and Meis1 competition for Pbx1 binding regulates protein stability and tumorigenesis [hP]

Project description:Prep1 is a tumor-suppressor, whereas Meis1 is an oncogene. We show that to perform these activities in MEFs both proteins competitively hetero-dimerize with Pbx1. Meis1 alone transforms Prep1-deficient fibroblasts while Prep1 overexpression inhibits Meis1 tumorigenicity. Pbx1 can therefore alternatively act as oncogene or tumor-suppressor. Prep1 post-translationally controls the level of Meis1 decreasing its stability by sequestering Pbx1. The different levels of Meis1 and the presence of Prep1 are followed at the transcriptional level by the induction of specific transcriptional signatures. The decrease of Meis1 prevents Meis1 interaction with Ddx3x and Ddx5, which are essential for Meis1 tumorigenesis, and modifies the growth promoting DNA binding landscape of Meis1 to the growth controlling landscape of Prep1. Hence the key feature of Prep1 tumor inhibiting activity is the control of Meis1 stability.

2016-06-01 | GSE58802 | GEO

Prep1 and Meis1 competition for Pbx1 binding regulates protein stability and tumorigenesis [hM, hMP]

2014-03-05 | GSE54221 | GEO

Prep1 prevents premature adipogenesis of mesenchymal progenitors [RNA-seq]

Project description:Transcriptional regulators are crucial in adipocyte differentiation. We now show that the homeodomain-containing transcription factor Prep1 is a repressor of adipogenic differentiation since its down-regulation (DR) in both ex vivo bone marrow-derived mesenchymal stromal cells (MSC) and in vitro 3T3-L1 pre-adipocytes significantly increases their adipogenic differentiation ability. Prep1 acts at a stage preceding the activation of the differentiation machinery because its DR makes cells more prone to adipogenic differentiation even in the absence of the adipogenic inducers. Prep1 DR expands the DNA binding landscape of C/EBP(CAAT enhancer binding protein ) without affecting its expression or activation. The data indicate that Prep1 normally acts by restricting DNA binding of transcription factors to adipogenic enhancers, in particular C/EBP.

2017-12-06 | GSE100056 | GEO

Prep1 prevents premature adipogenesis of mesenchymal progenitors [ChIP-seq]

Project description:Transcriptional regulators are crucial in adipocyte differentiation. We now show that the homeodomain-containing transcription factor Prep1 is a repressor of adipogenic differentiation since its down-regulation (DR) in both ex vivo bone marrow-derived mesenchymal stromal cells (MSC) and in vitro 3T3-L1 pre-adipocytes significantly increases their adipogenic differentiation ability. Prep1 acts at a stage preceding the activation of the differentiation machinery because its DR makes cells more prone to adipogenic differentiation even in the absence of the adipogenic inducers. Prep1 DR expands the DNA binding landscape of C/EBPß(CAAT enhancer binding protein ß) without affecting its expression or activation. The data indicate that Prep1 normally acts by restricting DNA binding of transcription factors to adipogenic enhancers, in particular C/EBPß.

2017-12-06 | GSE100055 | GEO

Prep1 and Meis1 competition for Pbx1 binding regulates protein stability and tumorigenesis.

2014-03-05 | E-GEOD-54221 | biostudies-arrayexpress

Prep1 and Meis1 competition for Pbx1 binding regulates protein stability and tumorigenesis [hP]

2016-06-01 | E-GEOD-58802 | biostudies-arrayexpress