Ontology highlight
ABSTRACT:
PROVIDER: PRJNA744624 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15068114.fastq.gz | Fastqsanger.gz | |||
| SRR15068115.fastq.gz | Fastqsanger.gz |
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Project description:Type I interferon (IFN-I) is essential in the development of Systemic Lupus Erythematosus (SLE) and many other autoimmune diseases. To explore the metabolic regulations of IFN-I signaling pathway, we conducted a high through-put screening of a small molecule library and identified diosmetin as a potent compound for blocking IFN-I signaling. Diosmetin can ameliorate lupus-like autoimmune phenotypes in IFNα-accelerated NZB/NZW F1 lupus model and pristane-induced murine lupus model. Of note, diosmetin can block over-activated IFN-I signaling pathway in PBMCs from lupus patients by reducing the expression of CYP1B1. Our findings reveal a novel lipid metabolic regulation of IFN-I signaling and a potent alternative therapeutic target for autoimmune diseases with overactivated IFN-I signaling pathway.
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Project description:Type I interferon (IFN-I) is essential in the development of Systemic Lupus Erythematosus (SLE) and many other autoimmune diseases. To explore the metabolic regulations of IFN-I signaling pathway, we conducted a high through-put screening of a small molecule library and identified diosmetin as a potent compound for blocking IFN-I signaling. Diosmetin can ameliorate lupus-like autoimmune phenotypes in IFNα-accelerated NZB/NZW F1 lupus model and pristane-induced murine lupus model. Of note, diosmetin can block over-activated IFN-I signaling pathway in PBMCs from lupus patients by reducing the expression of CYP1B1. Our findings reveal a novel lipid metabolic regulation of IFN-I signaling and a potent alternative therapeutic target for autoimmune diseases with overactivated IFN-I signaling pathway.
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Project description:The equilibrium between cellular differentiation and proliferation is fundamental for tissue homeostasis. This is particularly important for the liver, a highly differentiated organ with systemic metabolic functions still endowed with unparalleled regenerative potential. Hepatocellular de-differentiation and uncontrolled proliferation are at the basis of liver carcinogenesis. We have identified SLU7, a pre-mRNA splicing regulator inhibited in hepatocarcinoma as a pivotal gene for hepatocellular homeostasis. SLU7 knockdown in human liver cells and mouse liver resulted in profound changes in pre-mRNA splicing and gene expression, leading to impaired glucose and lipid metabolism, refractoriness to key metabolic hormones, and reversion to a fetal-like gene expression pattern. Hepatocellular proliferation and a switch to a tumor-like glycolytic phenotype were also observed. Mechanistically, SLU7 governed the splicing and/or expression of essential genes for hepatocellular differentiation like SRSF3 and HNF4a, and was identified as a critical factor in cAMP-regulated gene transcription. SLU7 is therefore central for hepatocyte identity and quiescence. The expression of the splicing factor SLU7 in the human hepatocellular carcinoma cell line PLC/PRF/5 was knocked down with specific siRNAs (siSlu7). An irrelevant siRNA (siGL2) was used as negative control. The RNAto perfrom the array analysis was extracted 48h after transfection.
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Project description:Proprotein convertase subtilisin kexin type 9 (PCSK9) is a key regulator of LDL cholesterol metabolism and the target of lipid-lowering drugs. PCSK9 is mainly expressed in hepatocyte. Here, we show that PCSK9 is highly expressed in undifferentiated hiPSCs. PCSK9 inhibition in hiPSCs with the use of shRNA, CRISPR/cas9-mediated knockout or endogenous PCSK9 loss-of-function mutation R104C/V114A unveiled its new role as a potential cell cycle regulator through the NODAL signaling pathway. Indeed, PCSK9 inhibition leads to a decrease of SMAD2 phosphorylation and hiPSCs proliferation. Conversely, PCSK9 overexpression stimulates hiPSCs proliferation. PCSK9 can interfere with the NODAL pathway by regulating the expression of its endogenous inhibitor DACT2, which is involved in the TGFß-R1 lysosomal degradation. Using different PCSK9 constructs we show that PCSK9 interacts with DACT2 through its CHRD domain. Altogether these data highlight a new role of PCSK9 in cellular proliferation and development, beyond its canonical effect on lipid metabolism.
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