Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Single-cell RNAseq of mouse pancreatic cells treated with proliferative compounds

ABSTRACT: It is known that β-cell proliferation expands the β-cell mass during development and under certain hyperglycemic conditions in the adult, a process that may be used for β-cell regeneration in diabetes. Here we used a novel high-throughput technique in zebrafish and screened 3119 chemicals to determine whether they promoted β-cell proliferation. We identified HG-9-91-01, which was further confirmed to drive the proliferation of zebrafish, mouse, and human β-cells. HG-9-91-01 is an inhibitor of salt-inducible kinases (SIK), and β-cell specific overexpression of Sik1 blocked its effect on β-cell proliferation. Single-cell transcriptomic analyses of mouse β-cells demonstrated that HG-9-91-01 induced an early wave of ATF6-dependent unfolded protein response (UPR), which was not related to increased insulin expression. Additional mechanistic studies indicated that HG-9-91-01 induced multiple signaling effectors downstream of SIK inhibition, including CRTC, ATF6/IRE1, and mTOR, which integrated to collectively drive β-cell proliferation.

ORGANISM(S): Mus musculus

PROVIDER: GSE163972 | GEO | 2021/03/07

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

SIK2 phosphorylation in response to glucagon or insulin in murine hepatocytes

Project description:The phosphorylation state of human HA-tagged-SIK2, adenovirally introduced in murine hepatocytes (C57/BL/6 strain) was analysed in unstimulated and in response to glucagon- or insulin- treated conditions. Background:- LKB1 is a master kinase that regulates metabolism and growth through AMPK and 12 other closely-related kinases. Liver-specific ablation of LKB1 causes increased glucose production in hepatocytes in vitro and hyperglycaemia in fasting mice in vivo. The salt-inducible kinases (SIK1, 2 and 3), members of the AMPK-related kinase family, play a key role as gluconeogenic suppressor downstream of LKB1 in the liver. A selective SIK inhibitor (HG-9-91-01) promotes dephosphorylation of transcriptional co-activators CRTC2/3 resulting in enhanced gluconeogenic gene expression and glucose production in hepatocytes, an effect that is abolished when an HG-9-91-01-insensitive-mutant-SIK is introduced or LKB1 is ablated. Although SIK2 was proposed as a key regulator of insulin-mediated suppression of gluconeogenesis, we provide genetic evidence that liver-specific ablation of SIK2 alone has no effect on gluconeogenesis and insulin does not modulate SIK2 phosphorylation/activity. Collectively, we demonstrate that the LKB1-SIK pathway functions as a key gluconeogenic gatekeeper in the liver.

2014-08-08 | PXD001032 | Pride

A Parathyroid Hormone/Salt-Inducible Kinase Signaling Axis Controls Renal Vitamin D Activation and Organismal Calcium Homeostasis

Project description:The underling mechanism used by PTH to promote 1,25-vitamin D synthesis remains unknown. Here, we demonstrate that Salt Inducible Kinases (SIK) inhibitors drive renal 1,25-vitamin D production, as PTH inhibits SIK cellular activity by cAMP-dependent PKA phosphorylation. Although there are some evidence that PTH increases Cyp27b1 in proximal tubule epithelial cells, this has not been explored/confirmed using next generation sequencing. Thus, we are interested in identifying cell populations that are responsible for PTH- or SIK-inhibition induced Cyp27b1 increase.

2022-11-15 | GSE213316 | GEO

Activating transcription factor 6 is necessary and sufficient for alcoholic fatty liver disease in zebrafish

2014-05-01 | GSE56498 | GEO

Activating transcription factor 6 is necessary and sufficient for alcoholic fatty liver disease in zebrafish

Project description:ATF6 is a key regulator of the unfolded protein response. Through use of zebrafish and cultured cells we demonstrate that ATF6 drives fatty liver disease by interaction with fatty acid synthase (FASN). Total small RNA from livers of 5 dpf larval zebrafish were collected: 2 batches of Tg(fabp10:nls-mCherry) control larvae, 2 batches of ethanol-treated Tg(fabp10:nls-mCherry) larvae, and 1 batch of Tg(fabp10:nAtf6-cherry; cmlc2:GFP). Each batch was purified for preparation of high-throughput sequencing libraries.

2014-05-01 | E-GEOD-56498 | biostudies-arrayexpress

Tankyrase inhibitors target colorectal cancer stem cells via AXIN-dependent downregulation of c-KIT tyrosine kinase

Project description:Tankyrase, a poly(ADP-ribose) polymerase family member, destabilizes Axin and positively regulates the Wnt/β-catenin signaling. We demonstrated that tankyrase inhibitors can target the colorectal cancer stem-like cells. Tankyrase inhibitors efficiently suppress colorectal cancer stem-like cell proliferation via AXIN-dependent manner. We sorted CD44-positive COLO-320DM cells, which showed a characteristic of CSCs and were targeted by tankyrase inhibitors. We analyzed gene expression profile of CD44-positive cells (CD44-positive 01, 02, 03) and CD44-negative cells (CD44-negative 01, 02, 03).

2020-05-05 | GSE130750 | GEO

Flucloxacillin-modified proteins identified in primary human hepatocytes

Project description:Flucloxacillin is a β-lactam antibiotic associated with a high incidence of drug-induced liver injury. Although expression of HLA-B*57:01 increases susceptibility, little is known of the pathological mechanisms involved in the induction of the clinical phenotype. Irreversible protein modification is suspected to drive the reaction through the provision of flucloxacillin-modified peptides that are presented to T-cells by the protein encoded by the risk allele. In this study, the binding of flucloxacillin to human primary hepatocytes was characterized. Flucloxacillin was shown to bind to multiple intracellular proteins including major hepatocellular proteins (haemoglobin and albumin) and mitochondrial proteins (glutamate dehydrogenase and carbamoyl-phosphate synthase). Inhibition of membrane transporters multidrug resistance-associated protein 2 (MRP2) and P-glycoprotein (P-gp) appeared to reduce the levels of covalent binding. These flucloxacillin-modified intracellular proteins provide a potential source of neo-antigens for HLA-B*57:01 presentation by hepatocytes, that may drive CD8+ T-cell responses. More importantly, covalent binding to mitochondrial proteins, particularly those involved in the metabolism of both endogenous compounds and xenobiotics, could potentially affect their functional activity. This may increase cellular stress signalling and alter the regulatory threshold for activation of the adaptive immune system and thereby play an important role in determining the progression and severity of liver injury. Of particular interest, flucloxacillin binding to Lys50 on 14-3-3 proteins, a key residue within the 14-3-3 protein phospho-binding pocket, could potentially block its binding to signalling proteins as demonstrated by computational modelling, leading to regulating major cellular functions including cell proliferation, growth, apoptosis, autophagy, and cell motility.

2023-03-11 | PXD038581 | Pride

Amino acid priming of mTOR is essential for heart regeneration

Project description:For a short period of time in mammalian neonates, the mammalian heart can regenerate via cardiomyocyte proliferation. This regenerative capacity is largely absent in adults. In other organisms, including zebrafish, damaged hearts can regenerate throughout their lifespans. Many studies have been performed to understand the mechanisms of cardiomyocyte de-differentiation and proliferation during heart regeneration however, the underlying reason why adult zebrafish and young mammalian cardiomyocytes are primed to enter cell cycle have not been identified. Here we show the primed state of a pro-regenerative cardiomyocyte is dictated by its amino acid profile and metabolic state. Adult zebrafish cardiomyocyte regeneration is a result of amino acid-primed mTOR activation. Zebrafish and neonatal mouse cardiomyocytes display elevated glutamine levels, predisposing them to amino acid-driven activation of mTORC1. Injury initiates Wnt/β-catenin signalling that instigates primed mTORC1 activation, Lin28 expression and metabolic remodeling necessary for zebrafish cardiomyocyte regeneration. These studies reveal a unique mTORC1 primed state in zebrafish and mammalian regeneration competent cardiomyocytes.

2022-02-15 | PXD011791 | Pride

RNA-sequencing of mouse diabetic wounds treated with mast cell stabilizer MCS-01

Project description:To investigate global changes in gene expression patterns following treatment with DSCG or MCS-01 we performed RNA-sequencing and nanostring profiling analyses on Day 10 wounds. Differential expression analysis on pre-MCS-01 samples compared to blank identified 649 significantly altered genes at p value <0.05 and absolute fold change >=2. Similarly, in post-MCS-01 samples 954 genes were differentially expressed, of which 566 were down- and 388 up-regulated. DCSG treatment resulted in differential expression of 91 genes. RT-qPCR corroborated increased expression of NFκB and STAT3 with post-MCS-01 treatment. In addition, we compared miRNA expression between MCS-01 samples and controls. Pre-treatment significantly altered expression of 11 miRNAs, while post-treatment altered expression of 28 miRNAs. RT-qPCR confirmed miR-34c upregulation, while significant inverse correlations were found between miR-34c and selected target genes Lef-1, Myb, and Mycn.

2019-10-25 | GSE135915 | GEO

High Glucose Macrophage Exosomes Enhance Atherosclerosis by Driving Cellular Proliferation & Hematopoiesis [RNA-Seq]

Project description:Hyperglycemia is a recognized risk factor for cardiovascular complications in diabetes. While hyperglycemia is known to cause microRNA dysregulation that contributes to cellular activation, whether it can do so through intercellular communication via extracellular vesicles (EVs) is not known. We investigated whether EVs produced under hyperglycemic conditions could communicate signaling to drive atherosclerosis. We did so by treating Apoe−/−mice with exosomes produced by bone marrow‐derived macrophages (BMDM) exposed to high glucose (BMDM–HG-exo) or control. Repeated infusion of BMDM–HG-exo led to a robust increase in hematopoiesis leading to augmented circulating myeloid cell numbers. Four weeks of BMDM–HG-exo infusions increased atherosclerotic lesion sizes with an accumulation of macrophage and apoptotic cells in the aortic root. Transcriptome-wide analysis of naïve cultured macrophages treated with BMDM–HG-exo showed an upregulation of genes associated with cell proliferation. Furthermore, BMDM–HG-exo reprogramed energy metabolism in recipient macrophages with an upregulation of glycolytic activity. Plasma EVs isolated from human subjects with type II diabetes exerted similar cell signaling when incubated with cultured human macrophages. Lastly, profiling microRNA in BMDM–HG-exo and human diabetic plasma EVs converged on miR-486 as commonly enriched. In conclusion, our findings show that EVs serve to communicate detrimental

2021-08-18 | GSE162961 | GEO

High Glucose Macrophage Exosomes Enhance Atherosclerosis by Driving Cellular Proliferation & Hematopoiesis [miRNA-Seq]

2021-08-18 | GSE162958 | GEO