Viral like infection induces Human β cell dedifferentiation
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PROVIDER: PRJNA412009 | ENA |
REPOSITORIES: ENA
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Project description:LDHA induces β cell dedifferentiation in diabetes through metabolic epigenetic reprogramming
| PRJNA1214819 | ENA
Project description:Aims/hypothesis Pancreatic β cell dedifferentiation underlies the reversible reduction in β cell mass and function in diabetes. Interventional targets and adjuvant therapies to prevent/reverse β cell dedifferentiation and transdifferentiation may provide evidence to support the effective treatment of diabetes, while the underlying molecular mechanism remains elusive. Methods LDHA expression and activity were analysed in islets obtained from humans with type 2 diabetes, hyperglycaemic db/db mice, and a high-fat diet (HFD)-induced mouse model of diabetes. The impact of LDHA inhibition on β cell function and identity was investigated in high-fat diet (HFD) feeding mice and db/db mice. ChIP-seq and RNA-seq were used to investigate the specific molecular mechanism underlying the effect of LDHA on the H3K9la enhancement and beta cell function under glucotoxic conditions. Results We demonstrated that inhibition of LDHA effectively preserved β cell identity, which not only delay disease progression in prediabetic stage, but also improve insulin output and glucose homeostasis in diabetic models. Mechanistically, the activation of LDHA led to a marked increase in histone H3 lysine 9 lactylation (H3K9la) in the promoter region of the β cells dedifferentiation markers Sox9, Hes1 and Aldh1a3, and facilitated their transcription, thereby triggering β cell dedifferentiation as well as impaired glucose homeostasis and β cell function in mice. Conclusions/interpretation We unraveled the role of lactate dehydrogenase A (LDHA)-mediated metabolic and epigenetic reprogramming in β cell dedifferentiation during diabetes development. This study suggests that LDHA inhibition could be a novel therapeutic strategy for diabetes treatment.
2026-01-23 | GSE287858 | GEO
Project description:Aims/hypothesis Pancreatic β cell dedifferentiation underlies the reversible reduction in β cell mass and function in diabetes. Interventional targets and adjuvant therapies to prevent/reverse β cell dedifferentiation and transdifferentiation may provide evidence to support the effective treatment of diabetes, while the underlying molecular mechanism remains elusive. Methods LDHA expression and activity were analysed in islets obtained from humans with type 2 diabetes, hyperglycaemic db/db mice, and a high-fat diet (HFD)-induced mouse model of diabetes. The impact of LDHA inhibition on β cell function and identity was investigated in high-fat diet (HFD) feeding mice and db/db mice. ChIP-seq and RNA-seq were used to investigate the specific molecular mechanism underlying the effect of LDHA on the H3K9la enhancement and beta cell function under glucotoxic conditions. Results We demonstrated that inhibition of LDHA effectively preserved β cell identity, which not only delay disease progression in prediabetic stage, but also improve insulin output and glucose homeostasis in diabetic models. Mechanistically, the activation of LDHA led to a marked increase in histone H3 lysine 9 lactylation (H3K9la) in the promoter region of the β cells dedifferentiation markers Sox9, Hes1 and Aldh1a3, and facilitated their transcription, thereby triggering β cell dedifferentiation as well as impaired glucose homeostasis and β cell function in mice. Conclusions/interpretation We unraveled the role of lactate dehydrogenase A (LDHA)-mediated metabolic and epigenetic reprogramming in β cell dedifferentiation during diabetes development. This study suggests that LDHA inhibition could be a novel therapeutic strategy for diabetes treatment.
2026-01-23 | GSE287857 | GEO
Project description:LDHA induces β cell dedifferentiation in diabetes through metabolic epigenetic reprogramming [RNA-Seq]
| PRJNA1214817 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2018-01-31 | GSE104196 | GEO
Project description:We report RNA Seq analysis using Illumina nextSeq500 of human beta cells EndoC-BH1 treated with FGF2 to induce dedifferentiation. FGF2 treatment induced dedifferentiation of EndoC-BH1 cells. Indeed, we observed a strong decrease in expression of β-cell markers, (INS, MAFB, SLC2A2, SLC30A8 and GCK). Opposingly, we identifed positive markers of human β cell dedifferentiation, as attested by increased expression of mature β-cell disallowed transcription factors (MYC, HES1, SOX9 and NEUROG3). Interestingly, our temporal analysis revealed that loss of expression of β cell specific markers preceded the induction of β cell disallowed genes.
2018-02-26 | GSE103383 | GEO
Project description:In the pathogenesis of type 2 diabetes development of insulin resistance triggers an increase in pancreatic β-cell insulin secretion capacity and β-cell number. Failure of this compensatory mechanism is caused by a dedifferentiation of β-cells, which leads to insufficient insulin secretion and diabetic hyperglycemia. The β-cell factors that normally protect against dedifferentiation remain poorly defined. Here, through a systems biology approach, we identify the transcription factor Klf6 as a regulator of β-cell adaptation to metabolic stress. We show that inactivation of Klf6 in mouse β-cells blunts their proliferation induced by the insulin resistance of pregnancy, high-fat high-sucrose feeding, and insulin receptor antagonism. Transcriptomic analysis showed that Klf6 controls the expression of β-cell proliferation genes and, in the presence of insulin resistance, it prevents the down-expression of genes controlling mature β-cell identity and the induction of disallowed genes that impair insulin secretion; its expression also limits the transdifferentiation of β-cells into alpha cells. Our study identifies a new transcription factor that protects β-cells against dedifferentiation and which may be targeted to prevent diabetes development.
2020-03-01 | GSE137187 | GEO
Project description:Type 1 diabetes (T1D) is a chronic disease characterized by an autoimmune-mediated destruction of insulin-producing pancreatic β cells. Environmental factors such as viruses play an important role in the onset of T1D and interact with predisposing genes. Recent data suggest that viral infection of human islets leads to a decrease in insulin production rather than β cell death, suggesting loss of β cell identity. We undertook this study to examine whether viral infection could induce human β cell dedifferentiation. Using the functional human β cell line EndoC-βH1, we demonstrate that polyinosinic-polycytidylic acid (PolyI:C), a synthetic double-stranded RNA that mimics a byproduct of viral replication, induces a decrease in β cell-specific gene expression. In parallel with this loss, the expression of progenitor-like genes such as SOX9 was activated following PolyI:C treatment or enteroviral infection. SOX9 was induced by the NF-κB pathway and also in a paracrine non-cell-autonomous fashion through the secretion of IFN-α. Lastly, we identified SOX9 targets in human β cells as potentially new markers of dedifferentiation in T1D. These findings reveal that inflammatory signaling has clear implications in human β cell dedifferentiation.
| S-EPMC5821176 | biostudies-literature
Project description:Type 1 diabetes (T1D) is a chronic disease characterized by an autoimmune-mediated destruction of insulin-producing pancreatic β cells. Environmental factors such as viruses play an important role in the onset of T1D and interact with predisposing genes. Recent data suggest that viral infection of human islets leads to a decrease in insulin production rather than β cell death, suggesting loss of β cell identity. We undertook this study to examine whether viral infection could induce human ß cell dedifferentiation. Using the functional human β cell line EndoC-βH1, we demonstrate that polyinosinic-polycitidilic acid (PolyI:C), a synthetic double-stranded RNA that mimics a by-product of viral replication induces a decrease in β cell-specific gene expression. In parallel to this loss, the expression of progenitor-like genes such as SOX9 was activated following PolyI:C treatment or enteroviral infection. SOX9 was induced by the NF-kB pathway and also in a paracrine non-cell autonomous fashion through the secretion of IFNA. Finally, we identified new SOX9 targets in human β cells as new markers of dedifferentiation in T1D. These findings reveal that inflammatory signaling has clear implications in human β cell dedifferentiation.
2018-01-31 | GSE104190 | GEO
Project description:Virus infection may induce excessive interferon (IFN) responses that can lead to host tissue injury or even death. β-arrestin 2 regulates multiple cellular events through the G protein-coupled receptor (GPCR) signaling pathways. Here we demonstrate that β-arrestin 2 also promotes virus-induced production of IFN-β and clearance of viruses in macrophages. β-arrestin 2 interacts with cyclic GMP-AMP synthase (cGAS) and increases the binding of dsDNA to cGAS to enhance cyclic GMP-AMP (cGAMP) production and the downstreatm stimulator of interferon genes (STING) and innate immune responses. Mechanistically, deacetylation of β-arrestin 2 at Lys171 facilitates the activation of the cGAS–STING signaling and the production of IFN-β. In vitro, viral infection induces the degradation of β-arrestin 2 to facilitate immune evasion, while a β-blocker, carvedilol, rescues β-arrestin 2 expression to maintain the antiviral immune response. Our results thus identify a viral immune-evasion pathway via the degradation of β-arrestin 2, and also hint that carvedilol, approved for treating heart failure, can potentially be repurposed as an antiviral drug candidate.
2020-10-22 | GSE159735 | GEO