Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

An HDAC3-PROX1 Corepressor Module Acts on HNF4α to Control Hepatic Triglycerides

ABSTRACT: The histone deacetylase HDAC3 is a critical mediator of hepatic lipid metabolism, and liver-specific deletion of HDAC3 leads to fatty liver. To elucidate the underlying mechanism we developed a method of cross-linking followed by mass spectrometry to define a high-confidence HDAC3 interactome in vivo that includes the canonical NCoR/HDAC3 complex as well as Prospero-related homeobox 1 protein (PROX1). HDAC3 and PROX1 co-localize extensively on the mouse liver genome, and are co-recruited by Hepatocyte Nuclear Factor 4α (HNF4α). The HDAC3-PROX1 module controls the expression of a gene program regulating lipid homeostasis, and hepatic-specific ablation of either component increases triglyceride content in liver. These findings underscore the importance of specific combinations of transcription factors and coregulators in the fine tuning of organismal metabolism.

ORGANISM(S): Mus musculus

PROVIDER: GSE90533 | GEO | 2017/07/26

SECONDARY ACCESSION(S): PRJNA354961

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Fasting-sensitive SUMO-switch on Prox1 controls hepatic cholesterol metabolism

Project description:Accumulation of excess nutrients hampers proper liver function and is linked to non-alcoholic fatty liver disease (NAFLD) in obesity. However, the signals responsible for an impaired adaptation of hepatocytes to obesogenic dietary cues remain still largely unknown. Post-translational modification by the Small Ubiquitin-like Modifier (SUMO), allows for adynamic regulation of numerous processes including transcriptional reprograming. We demonstrate that specific SUMOylation of transcription factor Prox1 represents a nutrient-sensitive determinant of hepatic fasting metabolism. Prox1 was highly SUMOylated on lysine 556 in the liver of ad libitum and re-fed mice, while this modification was abolished upon fasting. In the context of diet-induced obesity, Prox1 SUMOylation became less sensitive to fasting cues. The hepatocyte-selective knock-in of a SUMOylation-deficient Prox1 mutant into mice fed a high-fat/high-fructose diet led to a reduction of systemic cholesterol levels, associated with the induction of liver bile acid detoxifying pathways during fasting. The generation of tools to maintain the nutrient-sensitive SUMO-switch on Prox1 may thus contribute to the development of “fasting-based” approaches for the preservation of metabolic health.

2023-10-24 | PXD041329 | Pride

PROX1 amplification predicts better prognosis of oral cancer and overexpression is associated with reduced tumor cell aggressiveness

Project description:Homeobox genes are a family of transcription factors that play a pivotal role in embryogenesis. Altered expression of Prospero-related homeobox gene 1 (PROX1) was recently associated with cancer, including oral squamous cell carcinoma (OSCC). This study aimed to investigate the functional role of PROX1 in oral carcinogenesis. PROX1 mRNA and protein expression levels were first investigated in 40 samples of OSCC and non-tumour margins. Methylation and amplification analysis was also performed to assess the epigenetic mechanisms involved in controlling PROX1 expression. OSCC cell line SCC9 was also transfected to stably express the PROX1 gene. Next, SCC9-PROX1-overexpressing cells and controls were then subjected to proliferation, differentiation, apoptosis, and microarray assays in vitro. OSCC samples had reduced PROX1 expression levels compared to non-tumour margins. PROX1 amplification was associated with better overall survival. PROX1 overexpression reduces cell proliferation by down-regulating cyclin D1 and up-regulating p21. PROX1-overexpressing cells also exhibited significantly reduced K18 and K19 expression.

2014-12-30 | GSE48265 | GEO

Liver transcriptome analysis of obese mice expressing a SUMO-deficient Prox1 (K556R) mutant in hepatocytes

Project description:Accumulation of excess nutrients hampers proper liver function and is linked to non-alcoholic fatty liver disease (NAFLD) in obesity. However, the signals responsible for an impaired adaptation of hepatocytes to obesogenic dietary cues remain still largely unknown. Post-translational modification by the Small Ubiquitin-like Modifier (SUMO), allows for a dynamic regulation of numerous processes including transcriptional reprograming. We demonstrate that specific SUMOylation of transcription factor Prox1 represents a nutrient-sensitive determinant of hepatic fasting metabolism. Prox1 is highly SUMOylated on lysine 556 in the liver of ad libitum and re-fed mice, while this modification is abolished upon fasting. In the context of diet-induced obesity, Prox1 SUMOylation becomes less sensitive to fasting cues. The hepatocyte-selective knock-in of a SUMOylation-deficient Prox1 mutant into mice fed a high-fat/high-fructose diet leads to a reduction of systemic cholesterol levels, associated with the induction of liver bile acid detoxifying pathways during fasting. The generation of tools to maintain the nutrient-sensitive SUMO-switch on Prox1 may thus contribute to the development of “fasting-based” approaches for the preservation of metabolic health.

2023-07-24 | GSE237593 | GEO

Liver transcriptome analysis of lean mice expressing a SUMO-deficient Prox1 (K556R) mutant in hepatocytes

Project description:Accumulation of excess nutrients hampers proper liver function and is linked to non-alcoholic fatty liver disease (NAFLD) in obesity. However, the signals responsible for an impaired adaptation of hepatocytes to obesogenic dietary cues remain still largely unknown. Post-translational modification by the Small Ubiquitin-like Modifier (SUMO), allows for a dynamic regulation of numerous processes including transcriptional reprograming. We demonstrate that specific SUMOylation of transcription factor Prox1 represents a nutrient-sensitive determinant of hepatic fasting metabolism. Prox1 is highly SUMOylated on lysine 556 in the liver of ad libitum and re-fed mice, while this modification is abolished upon fasting. In the context of diet-induced obesity, Prox1 SUMOylation becomes less sensitive to fasting cues. The hepatocyte-selective knock-in of a SUMOylation-deficient Prox1 mutant into mice fed a high-fat/high-fructose diet leads to a reduction of systemic cholesterol levels, associated with the induction of liver bile acid detoxifying pathways during fasting. The generation of tools to maintain the nutrient-sensitive SUMO-switch on Prox1 may thus contribute to the development of “fasting-based” approaches for the preservation of metabolic health.

2023-07-24 | GSE237590 | GEO

Prox1 determines hepatocyte versus cholangiocyte cell fate in liver progenitors

Project description:The mammalian liver, the largest solid organ in the body, accomplishes multiple critical roles necessary to preserve homeostasis. Human liver diseases are debilitating, costly and very often result in death. Uncovering developmental mechanisms that establish the complex architecture of the liver or generate the cellular diversity of this organ is necessary to develop more adequate methods to prevent, diagnose and cure liver diseases. This study investigated the role of the homeobox gene Prox1 during mouse hepatogenesis. We used microarrays to detail the global program of gene expression in liver samples from wildtype mice and Prox1 f/f;Foxa3Cre (conditional knockout) mice.

2013-03-15 | E-GEOD-36583 | biostudies-arrayexpress

Developmentally regulated isoform of HNF4α reprograms the adult liver

Project description:Hepatocyte Nuclear Factor 4α (HNF4α), master regulator of hepatocyte differentiation, is regulated by two promoters (P1 and P2). P1-HNF4α but not P2-HNF4α is expressed in normal adult liver in fed conditions. Both P1- and P2-HNF4α are expressed in fetal liver. P2-HNF4α expression is increased in fasted conditions, high fat diet, alcoholic liver and liver cancer. To determine the target genes of the P1- and P2-HNF4α isoforms, we compared P2-HNF4α-expressing exon swap mice (a7HMZ) to wildtype (WT) male mice. Liver ChIP-seq samples were taken at 10:30 AM (ZT 3.5)

2023-05-10 | GSE231538 | GEO

Developmentally regulated isoform of HNF4α reprograms the adult liver

Project description:Hepatocyte Nuclear Factor 4α (HNF4α), master regulator of hepatocyte differentiation, is regulated by two promoters (P1 and P2). P1-HNF4α but not P2-HNF4α is expressed in normal adult liver while both P1- and P2-HNF4α are expressed in fetal liver and liver cancer. To determine the physiological function of the HNF4α isoforms, we compared P2-HNF4α-expressing exon swap mice to wildtype (WT) using RNA-seq, ChIP-seq, proteomics, protein binding microarrays (PBMs) and metabolomics. P2-HNF4α orchestrates a distinct transcriptomic and metabolomic profile.

2018-08-31 | GSE117972 | GEO

Comparison of Prox1 expressing and Prox1 knockout intestinal tumors and the effect of A2V+CD40

Project description:Control or A2V+CD40 treated Prox1-proficient (AP) and Prox1-deficient (APP) tumors

2020-02-04 | GSE124716 | GEO

Gene expression in mouse liver depleted of HDAC3

Project description:Liver-specific depletion of HDAC3 leads to liver steatosis (fatty liver), suggesting disregulation of lipid metabolism. This is correlated with changes in lipid metabolic gene expression. Livers depleted of HDAC3 were removed from 12 week old male HDAC3 fl/fl mice (loxP sites flanking exon 4 to 7 of the HDAC3 gene encoding the catalytic domain of HDAC3) one week after the injection of AAV2/8-Tbg-Cre virus. Livers from the HDAC3 fl/fl mice injected with AAV2/8-Tbg-GFP were used as normal controls. mRNA was extracted from 100mg mouse liver samples and hybridized to Affymetrix microarrays. For each group (HDAC3 depleted liver and normal liver), we have 5 samples from different mice.

2011-03-11 | E-GEOD-25937 | biostudies-arrayexpress

PROX1 Orchestrates Tumor Metabolic Plasticity by Integrating LKB1-AMPK Signaling with BCAA Catabolism (ATAC-Seq)

Project description:Tumor cell metabolic plasticity is essential for tumor progression and therapeutic response, but the mechanism for regulation of metabolic plasticity remain poorly explored. Here, we identify PROX1 as an essential determinant for tumor metabolic plasticity. Notably, PROX1 is significantly reduced in response to metabolic stress or AMPK activation and is elevated in LKB1-deficient tumors in mice and human. Furthermore, the Ser79 phosphorylation of PROX1 by AMPK significantly alters its protein activity and allows a rapid recruitment of CUL4-DDB1 E3 ubiquitin ligase to promote PROX1 degradation under glucose starvation, a critical event that drives BCAA metabolism rewiring to suppress mTOR signaling. Importantly, PROX1 loss or Ser79 phosphorylation in HCC shows therapeutic resistance to metformin. Consistently, genetic ablation of PROX1 renders LKB1‐deficient KRAS-driven lung cancer resistant to phenformin treatment. Conversely, mice harboring non-phosphorylated PROX1 mutant or LKB1 mutant exhibit high PROX1 stabilization, promoting liver and lung cancer progression. Clinically, AMPK-PROX1 axis in human cancers is important for patient clinical outcomes. Collectively, our results demonstrate that the deficiency in the LKB1-AMPK axis in cancers reactivates PROX1 to sustain intracellular BCAA pools, resulting in enhanced mTOR signaling, and facilitating tumorigenesis and aggressiveness.

2022-09-27 | GSE214193 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data