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Splicing Factor SRSF1 Deficiency in the Liver Triggers NASH-like Pathology via R-Loop Induced DNA Damage and Cell Death

ABSTRACT: Regulation of RNA processing contributes profoundly to tissue development and physiology. Here, we report that serine-arginine-rich splicing factor 1 (SRSF1) is essential for hepatocyte function and survival. Although SRSF1 is mainly known for its many roles in mRNA metabolism, it is also crucial for maintaining genome stability. We show that acute liver damage in the setting of targeted SRSF1 deletion in mice is primarily mediated by the excessive formation of deleterious RNA-DNA hybrids (R-loops), which induce DNA damage. Combining hepatocyte-specific transcriptome, proteome, and RNA binding analyses, we demonstrate that widespread genotoxic stress following SRSF1 depletion results in global inhibition of mRNA transcription and protein synthesis, leading to impaired metabolism and trafficking of lipids. Accumulation of lipids in SRSF1-deficient hepatocytes is quickly followed by necroptotic cell death, inflammation, and fibrosis, resulting in NASH-like liver pathology. This pathogenesis is recapitulated in SRSF1-depleted human liver cancer cells illustrating a conserved and fundamental role for SRSF1 in preserving genome integrity and tissue homeostasis. Thus, our study uncovers how accumulation of detrimental R-loops impedes hepatocellular gene expression, triggering metabolic derangements and liver failure.

ORGANISM(S): Mus musculus

PROVIDER: GSE179634 | GEO | 2022/02/28

REPOSITORIES: GEO

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Splicing Factor SRSF1 Deficiency in the Liver Triggers NASH-like Pathology via R-Loop Induced DNA Damage and Cell Death

Project description:Regulation of RNA processing contributes profoundly to tissue development and physiology. The serine-arginine-rich splicing factor 1 (SRSF1) is essential for hepatocyte function and survival. Although SRSF1 is mainly known for its many roles in mRNA metabolism, it is also crucial for maintaining genome stability. We show that acute liver damage in the setting of targeted SRSF1 deletion in mice is primarily mediated by the excessive formation of deleterious RNA–DNA hybrids (R-loops), which induce DNA damage. Combining hepatocyte-specific transcriptome, proteome, and RNA binding analyses, we demonstrate that widespread genotoxic stress following SRSF1 depletion results in global inhibition of mRNA transcription and protein synthesis, leading to impaired metabolism and trafficking of lipids. Accumulation of lipids in SRSF1-deficient hepatocytes is quickly followed by necroptotic cell death, inflammation, and fibrosis, resulting in NASH-like liver pathology. This pathogenesis is recapitulated in SRSF1-depleted human liver cancer cells illustrating a conserved and fundamental role for SRSF1 in preserving genome integrity and tissue homeostasis. This data set contains a proteomic comparison of hepatocytes from wild type vs. acute knockout of SRSF1. The acute knockout was generated by injecting 8-week-old SRSF1 fl/fl mice with a viral vector expressing Cre under the control of the liver-specific thyroxine binding globulin (TBG) promoter (AAV8-TBG-iCre). Controls were generated by injecting AAV8-TBG-GFP viral vector. The hepatocytes were isolated 2 weeks post injection.

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Loss of canonical splicing factor SRSF1 in hepatocytes results in acute liver injury and regeneration

Project description:Post-transcriptional gene regulatory mechanisms (PTGRM) contribute profoundly to liver development and physiology. Alternative splicing is one of the earliest mechanisms of gene regulation acting on nascently transcribed mRNA. This process is mediated by a large class of proteins known as splicing factors. SRSF1 is a canonical splicing factor with roles in both constitutive and alternative splicing. While its biochemical activities have been studied extensively, its role in tissue physiology are not well defined. In this study we investigate the role of SRSF1 in liver physiology using hepatocyte-specific knock-out mice models. Hepatocyte-specific knock-out of SRSF1 was achieved in two ways; 1) SRSF1 floxed mice were crossed with AlbCre transgenic mice and 2) SRSF1 floxed mice were injected with AAV8-TBG-iCre viral vector. The latter model allowed for investigating acute changes in hepatocyte upon ablation of SRSF1. Both models exhibit acute liver injury with severe cellular damage, inflammation and lipid accumulation. Utilizing high-throughput transcriptome profiling on purified hepatocytes, we find acute loss of SRSF1 triggers activation of the p53 pathway and splicing dysregulation of genes involved in mRNA metabolism. Continuous hepatic injury in this model eventually triggers a regenerative response resulting in the upregulation of genes involved in proliferation and repopulation of the tissue parenchyma.

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SRSF1 is involved in alternative mRNA splicing in granulosa cell survival

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