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Wilson disease: intersecting DNA methylation and histone acetylation mechanisms affect gene expression regulation in a mouse model of hepatic copper accumulation

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE168972 | GEO | 2021/07/09

REPOSITORIES: GEO

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Wilson disease: intersecting DNA methylation and histone acetylation mechanisms affect gene expression regulation in a mouse model of hepatic copper accumulation [RNA-Seq]

Project description:Prior investigations of DNA methylation differences in WD liver and blood and in a WD mouse model revealed an epigenetic signature of WD that included the histone deacetylase, HDAC5. To test the hypothesis that histone deacetylation and acetylation might be altered with respect to copper overload and aberrant DNA methylation in WD, we used the Jackson Laboratory toxic milk model (tx-j) of WD to study the involvement of Class IIa histone deacetylases (HDAC4 and HDAC5) and histone acetylation (H3K9ac and H3K27ac), and the effects of copper chelator D-penicillamine (PCA) and/or methyl group donor choline on histone modification. Next, we related acetylation profiles of H3K27ac to gene expression changes in wilson disease by ChIP and RNA-seq.

2021-07-09 | GSE168833 | GEO

Wilson disease: intersecting DNA methylation and histone acetylation mechanisms affect gene expression regulation in a mouse model of hepatic copper accumulation [ChIP-Seq]

2021-07-09 | GSE168971 | GEO

Wilson Disease: Intersecting DNA Methylation and Histone Acetylation Regulation of Gene Expression in a Mouse Model of Hepatic Copper Accumulation.

Project description:Background & aimsThe pathogenesis of Wilson disease (WD) involves hepatic and brain copper accumulation resulting from pathogenic variants affecting the ATP7B gene and downstream epigenetic and metabolic mechanisms. Prior methylome investigations in human WD liver and blood and in the Jackson Laboratory (Bar Harbor, ME) C3He-Atp7btx-j/J (tx-j) WD mouse model revealed an epigenetic signature of WD, including changes in histone deacetylase (HDAC) 5. We tested the hypothesis that histone acetylation is altered with respect to copper overload and aberrant DNA methylation in WD.MethodsWe investigated class IIa HDAC4 and HDAC5 and H3K9/H3K27 histone acetylation in tx-j mouse livers compared with C3HeB/FeJ (C3H) control in response to 3 treatments: 60% kcal fat diet, D-penicillamine (copper chelator), and choline (methyl group donor). Experiments with copper-loaded hepatoma G2 cells were conducted to validate in vivo studies.ResultsIn 9-week tx-j mice, HDAC5 levels increased significantly after 8 days of a 60% kcal fat diet compared with chow. In 24-week tx-j mice, HDAC4/5 levels were reduced 5- to 10-fold compared with C3H, likely through mechanisms involving HDAC phosphorylation. HDAC4/5 levels were affected by disease progression and accompanied by increased acetylation. D-penicillamine and choline partially restored HDAC4/5 and H3K9ac/H3K27ac to C3H levels. Integrated RNA and chromatin immunoprecipitation sequencing analyses revealed genes regulating energy metabolism and cellular stress/development, which, in turn, were regulated by histone acetylation in tx-j mice compared with C3H mice, with Pparα and Pparγ among the most relevant targets.ConclusionsThese results suggest dietary modulation of class IIa HDAC4/5, and subsequent H3K9/H3K27 acetylation/deacetylation can regulate gene expression in key metabolic pathways in the pathogenesis of WD.

| S-EPMC8487080 | biostudies-literature

Wilson disease: intersecting DNA methylation and histone acetylation mechanisms affect gene expression regulation in a mouse model of hepatic copper accumulation

Project description:Wilson disease: intersecting DNA methylation and histone acetylation mechanisms affect gene expression regulation in a mouse model of hepatic copper accumulation

| PRJNA714683 | ENA

Wilson disease: intersecting DNA methylation and histone acetylation mechanisms affect gene expression regulation in a mouse model of hepatic copper accumulation [ChIP-Seq]

Project description:Wilson disease: intersecting DNA methylation and histone acetylation mechanisms affect gene expression regulation in a mouse model of hepatic copper accumulation [ChIP-Seq]

| PRJNA714687 | ENA

Wilson disease: intersecting DNA methylation and histone acetylation mechanisms affect gene expression regulation in a mouse model of hepatic copper accumulation [RNA-Seq]

Project description:Wilson disease: intersecting DNA methylation and histone acetylation mechanisms affect gene expression regulation in a mouse model of hepatic copper accumulation [RNA-Seq]

| PRJNA714118 | ENA

Specific changes of liver transcriptome in the early stages of copper accumulation in the mouse model of wilson disease

Project description:Wilson disease (WD) is a severe metabolic disorder caused by genetic inactivation of copper-transporting ATPase ATP7B. In WD, copper accumulates in several tissues, particularly in the liver, inducing marked time-dependent pathological changes. To identify initial events in the copper-dependent development of liver pathology we utilized the Atp7b-/- mice, an animal model for WD. Analysis of mRNA from livers of control and Atp7b-/- 6 weeks-old mice using oligonucleotide arrays revealed specific changes of the transcriptome at this stage of copper accumulation. Few messages (29 up-regulated and 46 down-regulated) change their abundance more than 2-fold pointing to the specific effect of copper on gene expression/mRNA stability. The gene ontology analysis revealed copper effects on distinct metabolic pathways. Keywords: comparative genomic hybridization

2006-12-19 | GSE5348 | GEO

Transcription profiling of mouse model of Wilson disease reveals specific changes of liver transcriptome in the early stages of copper accumulation

2008-06-13 | E-GEOD-5348 | biostudies-arrayexpress

TRANSCRIPTIONAL REMODELLING IN RESPONSE TO CHANGING COPPER LEVELS IN WILSON DISEASE MODEL OF SACCHAROMYCES CEREVISIAE

Project description:A 3 x 2 factorial design was used to elucidate the genome-wide transcriptional response to the deletion of yeast ortholog of Wilson and Menkes disease causing gene; CCC2, at changing copper levels. Homozygous deletion mutant of CCC2, which encodes Cu+2 transporting P-type ATPase required to export copper from the cytosol into the extracytosolic compartment, and the reference strain were cultivated in fully controlled fermenters in duplicates in glucose-rich defined medium containing three different levels of copper. The three different copper concentrations were selected such that; copper deficient condition, which was prepared by excluding the CuSO4.7H2O from the defined medium, low copper or adequate copper concentration, which is the standard amount of copper in defined medium (0.04 ?M) and high copper concentration (0.5 mM), which was able to restore respiration deficiency in ccc2?/ccc2? strain.

2013-09-02 | E-MEXP-3927 | biostudies-arrayexpress

Near-infrared fluorescent sensor for in vivo copper imaging in a murine Wilson disease model.

Project description:Copper is an essential metal nutrient that is tightly regulated in the body because loss of its homeostasis is connected to severe diseases such as Menkes and Wilson diseases, Alzheimer's disease, prion disorders, and amyotrophic lateral sclerosis. The complex relationships between copper status and various stages of health and disease remain challenging to elucidate, in part due to a lack of methods for monitoring dynamic changes in copper pools in whole living organisms. Here we present the synthesis, spectroscopy, and in vivo imaging applications of Coppersensor 790, a first-generation fluorescent sensor for visualizing labile copper pools in living animals. Coppersensor 790 combines a near-infrared emitting cyanine dye with a sulfur-rich receptor to provide a selective and sensitive turn-on response to copper. This probe is capable of monitoring fluctuations in exchangeable copper stores in living cells and mice under basal conditions, as well as in situations of copper overload or deficiency. Moreover, we demonstrate the utility of this unique chemical tool to detect aberrant increases in labile copper levels in a murine model of Wilson disease, a genetic disorder that is characterized by accumulation of excess copper. The ability to monitor real-time copper fluxes in living animals offers potentially rich opportunities to examine copper physiology in health and disease.

| S-EPMC3289337 | biostudies-literature

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