Alterations in the hepatocyte epigenetic landscape in steatosis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA967364 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24440816.fastq.gz | Fastqsanger.gz | |||
| SRR24440817.fastq.gz | Fastqsanger.gz | |||
| SRR24440818.fastq.gz | Fastqsanger.gz | |||
| SRR24440819.fastq.gz | Fastqsanger.gz | |||
| SRR24440820.fastq.gz | Fastqsanger.gz |
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Project description:Fatty liver disease or the accumulation of fat in the liver, has been reported to affect the global population. This comes with an increased risk for the development of fibrosis, cirrhosis, and hepatocellular carcinoma. Yet, little is known about the effects of a diet containing high fat and alcohol towards epigenetic aging, with respect to changes in transcriptional and epigenomic profiles. In this study, we took up a multi-omics approach and integrated gene expression, methylation signals, and chromatin signals to study the epigenomic effects of a high-fat and alcohol-containing diet on mouse hepatocytes. We identified four relevant gene network clusters that were associated with relevant pathways that promote steatosis. Using a machine learning approach, we predict specific transcription factors that might be responsible to modulate the functionally relevant clusters. Finally, we discover four additional CpG loci and validate aging-related differential CpG methylation. Differential CpG methylation linked to aging showed minimal overlap with altered methylation in steatosis.
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Project description:Liver steatosis is a common cause of chronic liver disease. To investigate the molecular basis of hepatic steatosis, low-density lipoprotein receptor-deficient (LDLR -/-) mice were fed Western diet (WD, 42% of calories from fat) for 5, 14, or 42 days and evaluated against mice fed a normal laboratory diet. Histological analyses revealed that steatosis was detected as early as 14 days of WD feeding. Bulk RNA sequencing demonstrated that WD feeding altered liver transcriptomes related to inflammation and cell adhesion consistent with the progression of liver steatosis. Previous studies determined that hepatocyte-specific deficiency of angiotensinogen (AGT), the unique substrate of the renin-angiotensin system (RAS), alleviates WD-induced hepatic steatosis in mice. However, the effects of hepatic AGT deficiency were not mimicked by pharmacological inhibition of the RAS, and the molecular mechanisms by which AGT deficiency protects against WD-induced steatosis is unknown. Therefore, liver transcriptomes were compared between hepatocyte-specific AGT deficient mice (hepAGT -/-) and their wild-type littermates (hepAGT +/+) after 14 days of WD feeding. Gene ontology analyses showed that upregulated genes in hepAGT -/- mice were enriched for metabolic processes and downregulated genes were enriched for cell division pathways. The integration analysis of the two RNA sequencing data identified 5 key genes, Smpd3, Dtl, Cdc6, Mki67, and Top2a, which were primarily associated with cell division processes in hepAGT +/+ mice and were suppressed in hepAGT -/- mice. In conclusion, hepatic AGT deficiency downregulated genes related to cell division during the progression of liver steatosis.
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