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RNA sequencing of control and PTPN2 knocked down transcriptomes in EndoC- H1 cells with or without the treatment of pro-inflammatory cytokines

ABSTRACT: Type 1 diabetes (T1D) results from autoimmune destruction of β-cells in the pancreas. Protein tyrosine phosphatases (PTPs) are candidate genes for T1D and play a key role in autoimmune disease development and β-cell function. Here, we assessed the global protein and individual PTP profile in the pancreas from diabetic NOD mice treated with anti-CD3 monoclonal antibody and IL-1 receptor antagonist (IL-1RA). The treatment reversed hyperglycemia compared to the anti-CD3 alone control group. We observed enhanced expression of PTPN2, a T1D candidate gene, and endoplasmic reticulum (ER) chaperones in islets from mice with reversed diabetes. To address the functional role of PTPN2 in β-cells, we generated PTPN2 deficient stem cell-derived β-like and human EndoC-βH1 cells. Mechanistically, we demonstrated that PTPN2 inactivation in β-cells exacerbates the type I and type II IFN signalling networks, and the potential progression towards autoimmunity. Moreover, we established the capacity of PTPN2 to modulate the Ca2+-dependent unfolded protein response in β-cells. Adenovirus-induced overexpression of PTPN2 decreased BiP expression and partially protected from ER-stress induced β-cell death. Our results postulate PTPN2 as a key protective factor in β-cells during inflammation and ER stress in autoimmune diabetes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE172148 | GEO | 2022/01/21

REPOSITORIES: GEO

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Proteome and (ox)PTP profile analysis of diabetic NOD mouse under single (anti-CD3) or combined (anti-CD3 + IL1RA) treatment

Project description:Type 1 diabetes (T1D) results from autoimmune destruction of β cells in the pancreas. Protein tyrosine phosphatases (PTPs) are candidate genes for T1D and play a key role in autoimmune disease development and β-cell function. Here, we assessed the global protein and individual PTP profile in the pancreas of diabetic NOD mice treated with anti-CD3 mAb and IL-1RA combination therapy. The treatment reversed hyperglycemia compared to the anti-CD3 alone control group. We observed enhanced expression of PTPN2, a T1D candidate gene, and endoplasmic reticulum (ER) chaperones in the islets from cured mice.

2022-11-10 | PXD025394 | Pride

PTPN2 regulates metabolic flux to affect beta cell susceptibility to inflammatory stress

Project description:Protein tyrosine phosphatase N2 (Ptpn2) is a type 1 diabetes (T1D) candidate gene identified from human genome-wide association studies. PTPN2 is highly expressed in human and murine islets and becomes elevated upon inflammation, suggesting that PTPN2 may be important for beta cell survival in the context of T1D. To test whether PTPN2 contributed to beta cell dysfunction in an inflammatory environment, we generated a beta cell-specific deletion of Ptpn2 in mice (Ptpn2 βKO). While unstressed animals exhibit normal metabolic profiles, streptozotocin (STZ) Ptpn2 βKO mice display marked increase in hyperglycemia and death due to exacerbated beta cell loss. Furthermore, cytokine treated Ptpn2 KO islets resulted in mitochondrial defects and reduced glucose-induced metabolic flux, suggesting beta cells lacking Ptpn2 are more susceptible to inflammatory stress associated with T1D due to compromised metabolic fitness.

2023-12-01 | GSE215852 | GEO

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Project description:As early as one month of age, non-obese diabetic (NOD) mice feature pancreatic infiltration of autoreactive T lymphocytes, which destruct insulin-producing beta cells, leading to autoimmune diabetes mellitus (T1D) within eight months. Thus, we hypothesized that during the development of T1D, the transcriptional modulation of immune reactivity genes, as well as, modulation of microRNAs (miRNAs) may occur during thymocytes mature into peripheral CD3+ T lymphocytes. Our aim is to analyze the transcriptional modulation of mRNA and microRNAs during development of thymocytes into peripheral CD3+ T lymphocytes in the context of the emergence of T1D.

2011-07-01 | E-MEXP-3235 | biostudies-arrayexpress

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2022-10-14 | PXD031966 | Pride

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2012-07-31 | E-MEXP-3572 | biostudies-arrayexpress

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Project description:Over 90% of disease associated single nucleotide polymorphisms (SNPs) identified by genome wide association studies (GWAS) are noncoding variants. Platform to efficiently validate the biological function of variants thus discovered remain distinctly lacking. Here, we used β-like cells derived from isogenic human pluripotent stem cells (hPSCs), carrying the type 1 diabetes (T1D)-associated noncoding SNP rs2542151T>G or the knockout of the SNP-associated gene PTPN2−/−, to systematically examine the role of the T1D associated noncoding variant in β cell function and survival. PTPN2−/− and rs2542151T>G both decrease insulin production and elevate cell apoptosis in vitro as well as in vivo. A high content chemical screen identified sodium butyrate, a short-chain fatty acid, to rescue the defects of PTPN2−/−and rs2542151G/G β-like cells in vitro and a humanized mouse model. The combined phosphoproteomics, proteomics and RNA-seq analyses discovered a LAMIN A/HDAC/ERK/complex 1 axis as the downstream pathway of PTPN2 to control β cell survival. Together, this study proved the principle to apply hPSC-derived β cells to study diabetes associated noncoding SNP, and identified a drug candidate for the precision therapy of T1D.

2021-03-22 | GSE166785 | GEO

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Project description:Type 1 Diabetes (T1D) is considered to be a Th1 autoimmune disease characterised by an absolute lack of insulin caused by an autoimmune destruction of the insulin producing pancreatic beta cells. Th1 lymphocytes are responsible for the infiltration of the islets of Langerhans and for the cytokine release that supports cytotoxic (Tc) lymphocytes to mediate destruction of the beta cells. The preclinical disease stage is characterized by the generation of the self-reactive lymphocytes that infiltrate the pancreas and selectively destroy the insulin-producing beta cells present in the islets. Other cellular immune mechanisms regarding immunoregulation and antigen presentation and processing are involved in T1D pathogenesis as well. Our aim was to identify genes involved in the corresponding signalling cascades, especially those which may serve as promising diagnostic tools for the identification of persons in the prediabetic phase of the disease. We addressed the question by analysing gene expression profiles of freshly isolated peripheral blood mononuclear cells in type 1 diabetes patients, their first degree relatives divided according to their autoantibody status, and healthy controls. 9 T1D-patients versus 10 first degree relatives versus 10 healthy controls

2011-05-09 | E-GEOD-29142 | biostudies-arrayexpress

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2016-02-24 | PXD000859 | Pride

Development of type 1 diabetes mellitus T1D in NOD mice follows transcriptional activity of thymocytes and peripheral T lymphocytes

Project description:Non-obese diabetic (NOD) mice feature pancreatic infiltration of autoreactive T lymphocytes as early as 1 month of age, which destruct insulin-producing beta-cells to finally emerge autoimmune diabetes mellitus (T1D) within 8 months. In view, we hypothesized that during the development of T1D, transcriptional modulation of immune reactivity genes may occur as thymocytes mature toward peripheral T lymphocytes. Transcriptome of thymocytes and peripheral CD3+ T lymphocytes from pre-diabetic or diabetic mice analyzed through microarray hybridizations allowed observation of 3,586 differentially expressed genes. Hierarchical clustering grouped mice according to age/T1D onset and genes to their ontology. Transcriptional activity of thymocytes toward peripheral T lymphocytes unraveled sequential participation of genes involved with CD4+/CD8+ T cell differentiation (Themis), tolerance induction (Foxp3), apoptosis (Fasl) to soon after T cell activation (IL4), while the emergence of T1D coincided with the expression of cytotoxicity (Crtam) and inflammatory response genes (Tlr) by peripheral T lymphocytes.

2011-03-03 | E-MEXP-3047 | biostudies-arrayexpress

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