Splicing Factor SRSF1 Deficiency in the Liver Triggers NASH-like Pathology via R-Loop Induced DNA Damage and Cell Death
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA744429 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15058673_1.fastq.gz | Fastqsanger.gz | |||
| SRR15058673_2.fastq.gz | Fastqsanger.gz | |||
| SRR15058674_1.fastq.gz | Fastqsanger.gz | |||
| SRR15058674_2.fastq.gz | Fastqsanger.gz | |||
| SRR15058675.fastq.gz | Fastqsanger.gz |
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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.
2023-03-11 | PXD027035 | Pride
Project description: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.
2022-02-28 | GSE179634 | GEO
Project description: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 associated with 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. Lipid accumulation in SRSF1-deficient hepatocytes is followed by necroptotic cell death, inflammation, and fibrosis, resulting in NASH-like liver pathology. Importantly, SRSF1-depleted human liver cancer cells recapitulate this pathogenesis, illustrating a conserved and fundamental role for SRSF1 in preserving genome integrity and tissue homeostasis. Thus, our study uncovers how the accumulation of detrimental R-loops impedes hepatocellular gene expression, triggering metabolic derangements and liver damage.
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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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Project description:Peripheral artery disease is a severe ischemic vascular pathology without effective pharmacological approaches and improving angiogenesis to recover blood perfusion is a promising therapeutic strategy. Endothelial cells (ECs) are the primary cell type contributing to angiogenesis in response to ischemia. However, the molecular mechanisms regulating ischemia-induced angiogenesis remain elusive. We used a discovery-driven approach to identify elevated Peripheral artery disease is a severe ischemic vascular pathology without effective pharmacological approaches and improving angiogenesis to recover blood perfusion is a promising therapeutic strategy. Endothelial cells (ECs) are the primary cell type contributing to angiogenesis in response to ischemia. However, the molecular mechanisms regulating ischemia-induced angiogenesis remain elusive. We used a discovery-driven approach to identify elevated serine/arginine splicing factor 1 (SRSF1) expression in endothelial cells after ischemia. Proteomic analyses identified endogenous SRSF1 accumulated in ECs of the ischemic muscle and responded to hypoxia. Mice deficient in endothelial SRSF1 exhibited impaired blood flow recovery and impaired new capillary formation following HLI. Importantly, overexpression of SRSF1 enhanced blood flow recovery and angiogenesis after HLI. SRSF1 overexpression facilitated, while SRSF1 knockdown suppressed, the angiogenic function of human ECs. To explore the mechanism the mechanisms contributing to SRSF1-promoted endothelial angiogenesis,we conducted transcriptome RNA-seq searching for downstream molecules and verified it through RNA-pull down and chromatin immunoprecipitation qPCR analysis. We performed enhanced crosslinking and immunoprecipitation (eCLIP)-seq to profile the global SRSF1-binding sites on RNAs in HUVECs. Mechanistically, SRSF1 modulated ATF3 alternative splicing, wherein SRSF1 directly bound to ATF3 pre-mRNA and elevated full-length ATF3 transcript at the expense of truncated ATF3Δzip2 transcript, and in turn, ATF3 directly bound to the KLF2 promoter and suppressed KLF2-S1PR1 signaling, through which mediated the SRSF1-promoted endothelial tube formation and angiogenesis. Additionally, alprostadil, the prostaglandin E1 analog, could activate the SRSF1 signaling to improve endothelial angiogenesis in vitro and in vivo. Our findings identified SRSF1 as a novel regulator of ischemia-induced angiogenesis that enhances endothelial angiogenic functions by regulating the ATF3-KLF2/SIPR1 pathway. These results suggest that modulation of endothelial SRSF1 may represent a promising therapeutic approach for treating ischemic vascular diseases.
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