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Changes in nucleosome occupancy associated with metabolic alterations in aged mammalian liver [ChIP-seq]

ABSTRACT: Aging is accompanied by physiological impairments, which, in insulin-responsive tissues, including the liver, predispose individuals to metabolic disease. However, the molecular mechanisms underlying these changes remain largely unknown. Here, we analyze genome-wide profiles of RNA and chromatin organization in the liver of young (3 months) and old (21 months) mice. Transcriptional changes suggest that de-repression of the nuclear receptors PPARα, PPARγ, and LXRα in aged mouse liver leads to activation of targets regulating lipid synthesis and storage, whereas age-dependent changes in nucleosome occupancy are associated with binding sites for both known regulators (forkhead factors and nuclear receptors) and for novel candidates associated with nuclear lamina (Hdac3 and Srf) implicated to govern metabolic function of aging liver. Winged-helix factor Foxa2 and nuclear receptor co-repressor Hdac3 exhibit reciprocal binding pattern at PPARα targets contributing to gene expression changes that lead to steatosis in aged liver. Genome-wide location analysis (ChIP-Seq) of Foxa2 and Hdac3 from young (3 months) and old (21 months) mouse livers

ORGANISM(S): Mus musculus

SUBMITTER: Irina Bochkis

PROVIDER: E-GEOD-60393 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Nucleosome occupancy profiles in young and old mouse liver [MNase-Seq]

Project description:Aging is accompanied by physiological impairments, which, in insulin-responsive tissues, including the liver, predispose individuals to metabolic disease. However, the molecular mechanisms underlying these changes remain largely unknown. Here, we analyze genome-wide profiles of RNA and chromatin organization in the liver of young (3 months) and old (21 months) mice. Transcriptional changes suggest that de-repression of the nuclear receptors PPARM-NM-1, PPARM-NM-3, and LXRM-NM-1 in aged mouse liver leads to activation of targets regulating lipid synthesis and storage, whereas age-dependent changes in nucleosome occupancy are associated with binding sites for both known regulators (forkhead factors and nuclear receptors) and for novel candidates associated with nuclear lamina (Hdac3 and Srf) implicated to govern metabolic function of aging liver. Winged-helix factor Foxa2 and nuclear receptor co-repressor Hdac3 exhibit reciprocal binding pattern at PPARM-NM-1 targets contributing to gene expression changes that lead to steatosis in aged liver. Genome-wide nucleosome profiles (MNase-Seq) from young (3 months) and old (21 months) mouse livers

2014-10-23 | E-GEOD-58005 | biostudies-arrayexpress

Changes in nucleosome occupancy associated with metabolic alterations in aged mammalian liver [ChIP-seq]

Project description:Aging is accompanied by physiological impairments, which, in insulin-responsive tissues, including the liver, predispose individuals to metabolic disease. However, the molecular mechanisms underlying these changes remain largely unknown. Here, we analyze genome-wide profiles of RNA and chromatin organization in the liver of young (3 months) and old (21 months) mice. Transcriptional changes suggest that de-repression of the nuclear receptors PPARα, PPARγ, and LXRα in aged mouse liver leads to activation of targets regulating lipid synthesis and storage, whereas age-dependent changes in nucleosome occupancy are associated with binding sites for both known regulators (forkhead factors and nuclear receptors) and for novel candidates associated with nuclear lamina (Hdac3 and Srf) implicated to govern metabolic function of aging liver. Winged-helix factor Foxa2 and nuclear receptor co-repressor Hdac3 exhibit reciprocal binding pattern at PPARα targets contributing to gene expression changes that lead to steatosis in aged liver.

2014-10-23 | GSE60393 | GEO

Nucleosome occupancy profiles in young and old mouse liver [MNase-Seq]

Project description:Aging is accompanied by physiological impairments, which, in insulin-responsive tissues, including the liver, predispose individuals to metabolic disease. However, the molecular mechanisms underlying these changes remain largely unknown. Here, we analyze genome-wide profiles of RNA and chromatin organization in the liver of young (3 months) and old (21 months) mice. Transcriptional changes suggest that de-repression of the nuclear receptors PPARα, PPARγ, and LXRα in aged mouse liver leads to activation of targets regulating lipid synthesis and storage, whereas age-dependent changes in nucleosome occupancy are associated with binding sites for both known regulators (forkhead factors and nuclear receptors) and for novel candidates associated with nuclear lamina (Hdac3 and Srf) implicated to govern metabolic function of aging liver. Winged-helix factor Foxa2 and nuclear receptor co-repressor Hdac3 exhibit reciprocal binding pattern at PPARα targets contributing to gene expression changes that lead to steatosis in aged liver.

2014-10-23 | GSE58005 | GEO

Genome-wide expression profiles in young and old mouse liver [RNA-seq]

Project description:Aging is accompanied by physiological impairments, which, in insulin-responsive tissues, including the liver, predispose individuals to metabolic disease. However, the molecular mechanisms underlying these changes remain largely unknown. Here, we analyze genome-wide profiles of RNA and chromatin organization in the liver of young (3 months) and old (21 months) mice. Transcriptional changes suggest that de-repression of the nuclear receptors PPARα, PPARγ, and LXRα in aged mouse liver leads to activation of targets regulating lipid synthesis and storage, whereas age-dependent changes in nucleosome occupancy are associated with binding sites for both known regulators (forkhead factors and nuclear receptors) and for novel candidates associated with nuclear lamina (Hdac3 and Srf) implicated to govern metabolic function of aging liver. Winged-helix factor Foxa2 and nuclear receptor co-repressor Hdac3 exhibit reciprocal binding pattern at PPARα targets contributing to gene expression changes that lead to steatosis in aged liver.

2014-10-23 | GSE57809 | GEO

Genome-wide expression profiles in young and old mouse liver [RNA-seq]

Project description:Aging is accompanied by physiological impairments, which, in insulin-responsive tissues, including the liver, predispose individuals to metabolic disease. However, the molecular mechanisms underlying these changes remain largely unknown. Here, we analyze genome-wide profiles of RNA and chromatin organization in the liver of young (3 months) and old (21 months) mice. Transcriptional changes suggest that de-repression of the nuclear receptors PPARÎ±, PPARÎ³, and LXRÎ± in aged mouse liver leads to activation of targets regulating lipid synthesis and storage, whereas age-dependent changes in nucleosome occupancy are associated with binding sites for both known regulators (forkhead factors and nuclear receptors) and for novel candidates associated with nuclear lamina (Hdac3 and Srf) implicated to govern metabolic function of aging liver. Winged-helix factor Foxa2 and nuclear receptor co-repressor Hdac3 exhibit reciprocal binding pattern at PPARÎ± targets contributing to gene expression changes that lead to steatosis in aged liver. Genome-wide expression profiles (RNA-Seq) from young (3 months) and old (21 months) mouse livers

2014-10-23 | E-GEOD-57809 | biostudies-arrayexpress

Redistribution of lamina-associated domains reshapes Foxa2 binding in development of NAFLD

Project description:Non-alcoholic fatty liver disease (NAFLD) is highly prevalent in type 2 diabetes mellitus and the elderly, impacting 40% of individuals over 70. Regulation of heterochromatin at the nuclear lamina has been associated with aging and age-dependent metabolic changes. We have shown that changes at the lamina in aged hepatocytes and laminopathy models lead to redistribution of lamina-associated domains (LADs), opening of repressed chromatin, and upregulation of genes regulating lipid synthesis and storage, culminating in fatty liver. Here we test the hypothesis that change in expression of lamina-associated proteins and nuclear shape leads to redistribution of LADs, followed by altered binding of pioneer factor FOXA2, uprregulation of lipid synthesis and storage, and culminating in steatosis in younger NAFLD patients (aged 21-51). Changes in nuclear morphology alter LAD partitioning and reduced lamin B1 signal correlates with increased FOXA2 binding prior to severe steatosis in young mice placed on Western det. Nuclear shape is also changed in younger NAFLD patients. LADs are redistrubted and Lamin B1 signal decreases similarly in mild and severe steatosis. In contrast, FOXA2 binding is similar in normal and NAFLD patients with moderate steatosis and is repositioned only in NAFLD patients with more severe lipid accumulation. Hence, changes at the nuclear lamina reshape FOXA2 binding with progression of the disease. Our results suggest a role for nuclear lamina in etiology of NAFLD, irrespective of aging, with potential for improved stratification of patients and novel treatments aimed at restoring nuclear lamina function.

2022-11-10 | GSE197399 | GEO

Pioneer factor Foxa2 enables ligand-dependent activation of type II nuclear receptors FXR and LXRa

Project description:Type II nuclear hormone receptors, such as FXR, LXR, and PPAR, which function in glucose and lipid metabolism and serve as drug targets for metabolic diseases, are permanently positioned in the nucleus regardless of the ligand status. Ligand activation of these receptors is thought to occur by co-repressor/co-activator exchange, followed by initiation of transcription. However, recent genome-wide location analysis showed that LXRα and PPARα binding in the liver is largely ligand-dependent. We hypothesized that pioneer factor Foxa2 evicts nucleosomes to enable ligand-dependent receptor binding. We show that chromatin accessibility, FXR binding and LXRα occupancy, and ligand-responsive activation of gene expression by FXR and LXRα require Foxa2. Unexpectedly, Foxa2 occupancy is drastically increased when either receptor, FXR or LXRα, is bound by an agonist. In addition, co-immunoprecipitation experiments demonstrate that Foxa2 interacts with either receptor in a ligand-dependent manner, suggesting that Foxa2 and the receptor bind DNA as an interdependent complex during ligand activation. Furthermore, PPARα binding is induced in Foxa2 mutants treated with FXR and LXR ligands, leading to activation of PPARα targets.

2021-07-12 | GSE149075 | GEO

Mus musculus

Project description:Changes at the nuclear lamina alter binding of pioneer factor Foxa2 in aged liver.

| PRJNA312834 | ENA

The class 3 PI3K coordinates autophagy and mitochondrial lipid catabolism by controlling nuclear receptor PPARα

Project description:The class 3 phosphoinositide 3-kinase (PI3K) is required for the lysosomal degradation by autophagy and vesicular trafficking, assuring adaptation to energy shortages. Mitochondrial lipid catabolism is another important energy source. Autophagy and mitochondrial metabolism are transcriptionally controlled by nutrient sensing nuclear receptors. However, it is not known whether the class 3 PI3K contributes to this regulation. Here we show that hepatocyte-specific inactivation of Vps15, the essential regulatory subunit of the class 3 PI3K, results in mitochondrial depletion and a failure to oxidize fatty acids. Mechanistically, the transcriptional activity of Peroxisome Proliferator Activated Receptor alpha (PPARα), a nuclear receptor that orchestrates fatty acid catabolism, is blunted in Vps15-deficient livers. We find PPARα transcriptional repressors Histone Deacetylase 3 (Hdac3) and Nuclear receptor co-repressor 1 (NCoR1) accumulated in Vps15-deficient livers due to defective autophagic flux. Pharmacologic activation of PPARα with a synthetic ligand, re-expression of its co-activator Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha (PGC-1α) or inhibition of Hdac3 restored mitochondrial biogenesis and lipid oxidation in Vps15-deficient hepatocytes. These findings reveal a role for the class 3 PI3K and autophagy in transcriptional coordination of mitochondrial metabolism.

2020-02-06 | E-MTAB-7685 | biostudies-arrayexpress

Transcriptome analysis reveals key genes and pathways that the nuclear receptor PPARα acts on vascular aging

Project description:Our research is helpful to understand the physiological and pathological level changes caused by the nuclear transcriptional receptor PPARα acts on vascular aging, to find the mechanism of the signaling pathway downstream of PPARα in VSMCs, and to determine which signaling pathway is mediated by PPARα

2023-03-31 | GSE198045 | GEO

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