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RNA-seq Analysis of Prmt1f/f and Lrat-Cre; Prmt1f/f Mouse Fibrotic Liver Transcriptomes

ABSTRACT: Purpose: To identify the alterations of genes transcriptional profile of livers obtained from Prmt1f/f mice and Lrat-Cre; Prmt1f/f mice treated with thioacetamide (TAA). Methods: Lrat-Cre mice were crossed with and Prmt1f/f mice to generate Lrat-Cre; Prmt1f/f mice. Prmt1f/f mice and Lrat-Cre; Prmt1f/f mice were treated with TAA (400mg/L, drinking water for 16 weeks) to induce liver fibrosis. Liver mRNA profiles of 10-week-old Prmt1f/f and Lrat-Cre; Prmt1f/f mice treated with TAA were generated by deep sequencing, using Illumina Novaseq 6000. We applied DESeq2 algorithm to filter the differentially expressed genes, after the significant analysis and FDR analysis under the following criteria: i) |log2FC| > 1 ; ii) Pvalue < 0.05. RT–PCR validation was performed using SYBR Green PCR Kit. Results: We identified 16916 transcripts in the livers of Prmt1f/f and Lrat-Cre; Prmt1f/f mice. 726 transcripts showed differential expression between Prmt1f/f and Lrat-Cre; Prmt1f/f livers, with a |log2FC| > 1 and P value < 0.05. Altered expression of 4 genes was confirmed by qRT–PCR. Conclusion: Our study represents the first detailed analysis of liver transcriptomes of Lrat-Cre; Prmt1f/f mice during liver fibrogenesis. RNA-seq based transcriptome analysis would provide us better understanding of complex biologic functions of Prmt1 in the hepatic stellate cell during the pricess of hepatic fibrogenesis in mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE196115 | GEO | 2022/02/07

REPOSITORIES: GEO

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Project description:Background & Aims: Inflammation in chronic liver diseases induces oxidative stress and thus may contribute to progression of liver injury, fibrosis, and carcinogenesis. The KEAP1/NRF2 axis is a major regulator of cellular redox balance. In the present study, we investigated whether the KEAP1/NRF2 system is involved in liver disease progression in human and mice. Methods: The clinical relevance of oxidative stress was investigated in a well-characterized cohort of NAFLD patients (n=63) by liver RNA sequencing and correlated with histological and clinical parameters. For functional analysis hepatocyte-specific NEMO knock-out (NEMO∆hepa) mice were crossed with hepatocyte-specific KEAP1 knock-out (KEAP1∆hepa) mice. Results: Immunohistochemical analysis of human liver sections showed increased oxidative stress and high NRF2 expression in patients with chronic liver disease. RNA sequencing of liver samples in a human pediatric NAFLD cohort revealed a significant increase of NRF2 activation correlating with the grade of inflammation, but not with the grade of steatosis, which could be confirmed in a second adult NASH cohort. In mice, microarray analysis revealed that KEAP1 deletion induces NRF2 target genes involved in glutathione metabolism and xenobiotic stress (e.g., Nqo1). Furthermore, deficiency of one of the most important antioxidants, glutathione (GSH), in NEMO∆hepa livers was rescued after deleting KEAP1. As a consequence, NEMO∆hepa/KEAP1∆hepa livers showed reduced apoptosis compared to NEMO∆hepa livers as well as a dramatic downregulation of genes involved in cell cycle regulation and DNA replication. Consequently, NEMO∆hepa/KEAP1∆hepa compared to NEMOΔhepa livers displayed decreased fibrogenesis, lower tumor incidence, reduced tumor number, and decreased tumor size. Conclusions: NRF2 activation in NASH patients correlates with the grade of inflammation, but not steatosis. Functional analysis in mice demonstrated that NRF2 activation in chronic liver disease is protective by ameliorating fibrogenesis, initiation and progression of hepatocellular carcinogenesis.

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RNA-seq Analysis of Prmt1f/f and Lrat-Cre; Prmt1f/f Mouse Fibrotic Liver Transcriptomes

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