Increased sulfation of bile acids in mice and human subjects with sodium taurocholate cotransporting polypeptide deficiency
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ABSTRACT:
PROVIDER: PRJNA510995 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8360780_1.fastq.gz | Fastqsanger.gz | |||
| SRR8360780_2.fastq.gz | Fastqsanger.gz | |||
| SRR8360790.fastq.gz | Fastqsanger.gz | |||
| SRR8360800.fastq.gz | Fastqsanger.gz | |||
| SRR8360771_1.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: To decipher the biochemical basis for the declining of total bile acids (TBA) levels in the late age of Slc10a1-/- mice, we performed a serial liver RNA-Seq analysis of mRNA expression with male mice at different ages. Methods: Liver mRNA profiles of 4-week, 8-week, 20-month-old wild-type (WT) and sodium taurocholate cotransporting polypeptide knockout (Slc10a1-/-) mice were generated by deep sequencing, in triplicate, quadruplicate or sextuplicate, using Illumina Hiseq-2500 platform. Clean mRNA-seq reads were aligned to the mouse reference genome (GRCm38) with TopHat (v2.0.13), guided by Ensembl gene annotation v83. Only uniquely aligned and properly paired reads were retained for further analysis. Gene-level read counts were calculated with HTseq (v0.6.1p1) with the union mode. Genes with less than a total of 11 non-normalized reads across all samples were excluded. Data normalization and statistical analysis of differential expression were performed with the DEseq2 (v1.10.0) R package. Pair-wise Spearman correlation between samples across all quantified genes used for hierarchical clustering. Results: At 4 weeks and 8 weeks, WT and Slc10a1-/- mice exhibited clear different pattern in terms of transcriptome similarity and were well separated, however, the difference was indistinguishable at 20 months.And changes of pathways involved in the metabolism of xenobiotics in Slc10a1-/- mice. Conclusions: Our study reveal that enhanced BA sulfation is a major mechanism for BA detoxification and elimination in Slc10a1-/- mice with hypercholanemia.
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Project description:miR-6126 downregulated expression level of sodium taurocholate cotransporting polypeptide (NTCP), a host cell receptor required for hepatitis B virus (HBV) entry.
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Project description:Chronic hepatitis B, C and D virus (HBV, HCV, HDV) infections are leading causes of liver disease and cancer worldwide. Although these viruses differ markedly in their life cycle and genomic organization, they exclusively infect hepatocytes. Recently, the sodium taurocholate cotransporting polypeptide (NTCP) was identified as the first functional receptor for HBV and HDV. Here, we report that NTCP also facilitates HCV entry into human hepatocytes, by augmenting the bile acids-mediated repression of IFN-stimulated genes (ISGs), including IFITM2 and IFITM3, to increase the susceptibility of cells to HCV entry. Furthermore, an HBV-derived preS1 peptide, known to bind NTCP and to inhibit bile acids uptake and HBV infection, inhibits HCV entry by enhancing the expression of ISGs. Our study highlights NTCP as a novel player linking bile acids metabolism to the interferon response in hepatocytes and establishes a role for NTCP in the entry process of multiple hepatotropic viruses, via distinct mechanisms. Collectively, these findings enhance our understanding of hepatitis virus-host interactions and suggest NTCP as an attractive antiviral target for HBV/HCV co-infection.
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Project description:Embryonic stem (ES) cells continuously decide whether to maintain pluripotency or differentiate. While exogenous LIF and BMP4 perpetuate a pluripotent state, less is known about factors initiating differentiation. We show that heparan sulfate (HS) proteoglycans are critical co-receptors for signals inducing ES cell differentiation. Genetic targeting of NDST1 and 2, two enzymes required for N-sulfation of proteoglycans, blocked differentiation. This phenotype was rescued by HS presented in trans or by soluble heparin. NaClO3-, which reduces sulfation of proteoglycans, potently blocked differentiation of wild type cells. Mechanistically, N-sulfation was identified to be critical for functional autocrine FGF4 signalling. Micro array analysis identified the pluripotency maintaining transcription factors Nanog, KLF2/4/8, Tbx3 and Tcf3 to be negatively regulated, whereas markers of differentiation such as Gbx2, Dnmt3b, FGF5 and Brachyury were induced by sulfation-dependent-FGFR signalling. We show that several of these genes are heterogeneously expressed in ES cells and targeting of heparan sulfation or FGFR-signalling facilitated a homogenous Nanog/KLF4/Tbx3 positive ES cell state. This finding suggests that the recently discovered heterogeneous state of ES cells is regulated by HS-dependent FGFR signalling. Similarly, culturing blastocysts with NaClO3- eliminated GATA6 positive primitive endoderm progenitors generating a homogenous Nanog positive inner cell mass. Functionally, reduction of sulfation robustly improved de novo ES cell derivation efficiency. We conclude that N-sulfated HS is required for FGF4 signalling to maintain ES cells primed for differentiation in a heterogeneous state. Inhibiting this pathway facilitates a more naïve ground state. Four groups with three biological replicates and a technical duplicate in each
2010-04-09 | E-GEOD-15974 | biostudies-arrayexpress
Project description:Hepatic cell lines serve as economical and reproducible alternatives for primary human hepatocytes. However, the utility of hepatic cell lines to examine bile acid homeostasis and cholestatic toxicity is limited due to abnormal expression and function of bile acid-metabolizing enzymes, transporters, and the absence of canalicular formation. Previously, addition of dexamethasone (DEX) and Matrigel™ overlay restored expression, localization, and function of the bile salt export pump (BSEP), and formation of bile canalicular-like structures in four-week cultures of HuH-7 human hepatoma cells. We present here an improved differentiation process with the addition of 0.5% dimethyl sulfoxide (DMSO), which increased the expression and function of the major bile acid uptake and efflux transporters, sodium taurocholate co-transporting polypeptide (NTCP) and BSEP, respectively, in two-week HuH-7 cell cultures. This in vitro model was further characterized for expression of cytochrome P450 enzymes (CYP450s), uridine 5'-diphospho-glucuronosyltransferase (UGTs) and transporters using quantitative targeted proteomics.
2022-10-14 | PXD031731 | Pride
Project description:Embryonic stem (ES) cells continuously decide whether to maintain pluripotency or differentiate. While exogenous LIF and BMP4 perpetuate a pluripotent state, less is known about factors initiating differentiation. We show that heparan sulfate (HS) proteoglycans are critical co-receptors for signals inducing ES cell differentiation. Genetic targeting of NDST1 and 2, two enzymes required for N-sulfation of proteoglycans, blocked differentiation. This phenotype was rescued by HS presented in trans or by soluble heparin. NaClO3-, which reduces sulfation of proteoglycans, potently blocked differentiation of wild type cells. Mechanistically, N-sulfation was identified to be critical for functional autocrine FGF4 signalling. Micro array analysis identified the pluripotency maintaining transcription factors Nanog, KLF2/4/8, Tbx3 and Tcf3 to be negatively regulated, whereas markers of differentiation such as Gbx2, Dnmt3b, FGF5 and Brachyury were induced by sulfation-dependent-FGFR signalling. We show that several of these genes are heterogeneously expressed in ES cells and targeting of heparan sulfation or FGFR-signalling facilitated a homogenous Nanog/KLF4/Tbx3 positive ES cell state. This finding suggests that the recently discovered heterogeneous state of ES cells is regulated by HS-dependent FGFR signalling. Similarly, culturing blastocysts with NaClO3- eliminated GATA6 positive primitive endoderm progenitors generating a homogenous Nanog positive inner cell mass. Functionally, reduction of sulfation robustly improved de novo ES cell derivation efficiency. We conclude that N-sulfated HS is required for FGF4 signalling to maintain ES cells primed for differentiation in a heterogeneous state. Inhibiting this pathway facilitates a more naïve ground state.
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Project description:The incidence and prevalence of inflammatory bowel disease (IBD) is gradually increasing. A high-fat diet (HFD) is known to disrupt intestinal homeostasis and aggravate IBD, yet the underlying mechanisms remain largely undefined. Here, a positive correlation between dietary fat intake and disease severity in both IBD patients and HFD-fed mice is observed. HFD induces a significant decrease in indole-3-acetic acid (IAA) and lead to intestinal barrier damage. Furthermore, IAA supplementation enhances the intestinal mucin sulfation and effectively alleviates colitis. Mechanistically, IAA upregulates key molecules involved in mucin sulfation, including Papss2 and Slc35b3, the synthesis enzyme and the transferase of 3'-phosphoadenosine-5'-phosphosulfate (PAPS), via the Aryl Hydrocarbon Receptor (AHR). More importantly, AHR can directly bind to the transcription start site of Papss2. Oral administration of Lactobacillus reuteri, which can produce IAA, contributes to protecting against colitis and promoting mucin sulfation, while the modified L. reuteri strain lacking the iaaM gene (LactobacillusΔiaaM) and the ability to produce IAA fails to exhibit such effects. Overall, IAA enhances intestinal mucin sulfation through AHR, contributing to the protection of intestinal homeostasis.
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Project description:Tumor extracellular matrices (ECM) exhibit aberrant changes in composition and mechanics compared to normal tissues. Proteoglycans (PG) are vital regulators of cellular signaling in the ECM with ability to modulate receptor tyrosine kinase (RTK) activation via their sulfated glycosaminoglycan (sGAG) side chains. However, their role on tumor cell behavior is controversial. Here, we demonstrate that PGs are heavily expressed in lung adenocarcinoma patients in correlation with invasive phenotype and poor prognosis. We developed an engineered human lung tumor model which recapitulate the increase of sGAGs in tumors in an organotypic matrix with independent control of stiffness, viscoelasticity, ligand density and porosity. Our model reveals that increased sulfation stimulates extensive proliferation, epithelial-mesenchymal transition and stemness in cancer cells. We identified the FAK-PI3K-Akt signaling axis as a mediator of sulfation-induced molecular changes in cells upon activation of a distinct set of RTKs within tumor-mimetic hydrogels. We employed an integrative omics and network modeling approach to uncover the transcriptomic landscape of tumor cells in response to sulfation which demonstrated resemblance to PG-rich patient tumors.
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Project description:Background & Aims: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer deaths in the United States. Tyrosine sulfation, catalyzed by the tyrosylprotein sulfotransferase 2 (TPST2), is a post-translational modification essential for protein-protein interactions and cellular functions. SLC35B2 is a key transporter that transports the universal sulfate donor 3’-phosphoadenosine 5’-phosphosulfate (PAPS) into the Golgi apparatus where the protein sulfation occurs. The goal of this study is to determine whether and how SLC35B2-TPST2 axis of tyrosine sulfation plays a role in PDAC. Methods: Gene expression was analyzed in PDAC patients and mice. Human PDAC MIA PaCa-2 and PANC-1 cells were used for in vitro studies. TPST2 deficient MIA PaCa-2 cells were generated to assess xenograft tumor growth in vivo. Mouse PDAC cells derived from the KrasLSL-G12D/+;Tp53L/+;Pdx1-Cre (KPC) mice were used to generate Tpst2 KO KPC cells to evaluate tumor growth and metastasis in vivo. Results: High expressions of SLC35B2 and TPST2 were correlated with poor PDAC patient survival. Knockdown of SLC35B2 or TPST2, or pharmacological inhibition of sulfation inhibited PDAC cell proliferation and migration in vitro. TPST2 deficient MIA PaCa-2 cells exhibited inhibited xenograft tumor growth. Orthotopic inoculation of Tpst2 KO KPC cells in mice showed inhibition of primary tumor growth, local invasion, and metastasis. Mechanistically, the integrin ITGB4 was found to be a novel substrate of TPST2. Inhibition of sulfation destabilizes ITGB4 protein, which may have accounted for the suppression of metastasis. Conclusions: Targeting the SLC35B2-TPST2 axis of tyrosine sulfation may represent a novel approach for therapeutic intervention of PDAC.
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Project description:Sulfation is a widespread modification for biomolecules so far poorly explored. Through cross phenotype meta-analysis for human bone mineral density up to 426824 participants and phenotypic characterization of multiple mutant mouse lines, we identified a causative role of the sulfate transporter SLC26A2 deficiency in osteoporosis. Ablation of SLC26A2 in osteoblasts caused severe bone loss and accumulation of immature bone cells and elicited a peculiar pericellular matrix (PCM) outcome, undersulfation coupled with decreased stiffness. Consequently, such altered chemophysical properties of PCM disrupted focal adhesion formation of osteoblasts. Based on bulk RNA sequencing and functional assays, we held a mechano-reciprocal tandem inhibition of FAK and YAP/TAZ responsible for impinged osteoblast maturation by SLC26A2 deficiency, where sulfation and stiffness of PCM were compromised by defective sulfate uptake and thus to exert an outside-in impediment to FAK-dependent YAP/TAZ activity required for osteoblast maturation. Moreover, pharmacological abrogation of the Hippo kinases and forced wheel-running concordantly ameliorated SLC26A2-deficient osteoporosis via enforcement of YAP/TAZ activity. Intriguingly, “guilt by association” analysis of single-cell sequencing data suggested coordination between sulfate metabolism, focal adhesion and YAP/TAZ activity during osteoblast-to-osteocyte transition. As seen in ovariectomized mice and patients with osteoporosis, tandem inhibition of FAK and YAP/TAZ apparently engaged in pathology of broader types of osteoporosis beyond SLC26A2 context. Collectively, these data unveil an unanticipated role of sulfation in developmental mechanoreciprocity between matrix and osteoblasts, which could be leveraged to prevent bone loss.
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