Maladaptive Positive Feedback Production of ChREBPβ Drives Glucotoxic β-Cell Failure
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ABSTRACT:
PROVIDER: PRJNA812532 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18213000_1.fastq.gz | Fastqsanger.gz | |||
| SRR18213000_2.fastq.gz | Fastqsanger.gz | |||
| SRR18213001_1.fastq.gz | Fastqsanger.gz | |||
| SRR18213001_2.fastq.gz | Fastqsanger.gz | |||
| SRR18213002_1.fastq.gz | Fastqsanger.gz |
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Project description:Preservation and expansion of β-cell mass is a therapeutic goal for diabetes. Here we show that the hyperactive isoform of carbohydrate response-element binding protein (ChREBPβ) is a nuclear effector of hyperglycemic stress occurring in β-cells in response to prolonged glucose exposure, high-fat diet, and diabetes. We show that transient positive feedback induction of ChREBPβ is necessary for adaptive β-cell expansion in response to metabolic challenges. Conversely, chronic excessive β-cell-specific overexpression of ChREBPβ results in loss of β-cell identity, apoptosis, loss of β-cell mass, and diabetes. Furthermore, β-cell "glucolipotoxicity" can be prevented by deletion of ChREBPβ. Moreover, ChREBPβ-mediated cell death is mitigated by overexpression of the alternate CHREBP gene product, ChREBPα, or by activation of the antioxidant Nrf2 pathway in rodent and human β-cells. We conclude that ChREBPβ, whether adaptive or maladaptive, is an important determinant of β-cell fate and a potential target for the preservation of β-cell mass in diabetes.
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Project description:Purpose: Test the role of ChREBPbeta in pancreatic beta cells using tools that distinguish ChREBPalpha and ChREBPbeta and loss and gain of function experiments, confirming its role in glucose toxicity and finding mitigation strategies. Methods: INS-1 832/13 cells cultured in 2 mM or 11 mM glucose were transduced with adenoviruses expressing GFP as control or ChREBPbeta. After 48 h, RNA was isolated and amplified via the NuGEN Ovation RNA-Seq System V2 prior to RNA sequencing. Human islets from non-diabetic and T2D subjects were transduced with adenovirus ZSGreen and cell sorted. RNA was isolated and subjected to RNAseq. Results: Overexpression of ChREBPbeta led to increased expression of cell cycle and apoptotic genes and a decrease in beta cell maturity genes. T2D human beta cells expressed an increased ratio of ChREBPbeta to ChREBPalpha compared to non-diabetics. Conclusions: ChREBPbeta is necessary for adaptive beta cell expansion, but drives glucose toxicity when overexpressed, mimicking the graded effect of Myc overexpression in beta cells.
2022-06-02 | GSE197864 | GEO
Project description:Transcriptomic analyses of ChREBPtotal-null mice and ChREBPβ-null mice
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Project description:Successful infection strategies must balance pathogen amplification and persistence. In Toxoplasma gondii, this is accomplished through differentiation into dedicated cyst-forming chronic stages that avoid clearance by the host immune system. The transcription factor BFD1 is both necessary and sufficient for stage conversion; however, its regulation is not understood. We examine five factors transcriptionally activated by BFD1. One of these is a cytosolic RNA-binding protein of the CCCH-type zinc finger family, which we name BFD2. Parasites lacking BFD2 fail to induce BFD1 and are consequently unable to fully differentiate in culture or in mice. BFD2 interacts with the BFD1 transcript under stress and deletion of BFD2 reduces BFD1 protein levels, but not mRNA abundance. The reciprocal effects on BFD2 transcription and BFD1 translation outline a positive feedback loop that enforces commitment to differentiation. BFD2 helps explain how parasites commit to the chronic gene-expression program and elucidates how the balance between proliferation and persistence is achieved over the course of infection.
2023-08-07 | PXD039648 | Pride
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Project description:Our previous work found a variety of cardiac stresses initiate site-specific cleavage of junctophilin-2 (JP2), an essential component of the E-C coupling apparatus, producing a 75-kDa N-terminal fragment (JP2NT) which unexpectedly translocates into cardiomyocyte nuclei and functions as a transcriptional repressor. We also determined that transgenic overexpression of JP2NT in cardiomyocytes attenuates pressure-overload induced hypertrophy and heart failure by blunting the induction of maladaptive transcripts. To test whether JP2NT could be utilized by gene therapy approaches for treating heart failure, we developed cardiotropic adeno-associated GFP and JP2NT expressing viruses for testing in a preclinical model of heart failure. Our results show that the transcriptional and pathological changes from pressure overload can be reduced through viral expression of JP2NT once hypertrophy and heart failure has already begun.
2022-09-06 | GSE189475 | GEO
Project description:Transcriptomic analyses of ChREBPtotal-null mice and ChREBPβ-null mice liver
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Project description:Synthetic systems that use positive feedback have been developed to control human disease vectors and crop pests. The tTAV system, which has been deployed in several insect species, relies on a positive feedback circuit that can be inhibited via dietary tetracycline. Although insects carrying tTAV fail to survive until adulthood in the absence of tetracycline, the exact reason for its lethality, as well as the transcriptomic effects of an active positive feedback circuit, remain unknown. Understanding what factors contribute to the variance in tTAV-associated mortality is likely to inform the development of insect control systems. In the present study, the OXI513a tTAV feedback circuit was introduced and verified into D. melanogaster. The tight tetracycline regulation of the system affords a convenient method to conduct a strain-by-strain assessment of the tTAV system and determine the transcriptomic effect, if any, of a positive feedback circuit. Transcriptomic analysis of four independent D. melanogaster tTAV insertion lines, in both adults and larvae, was conducted to examine the transcriptomic influence of the tTAV system. The tTAV lines and non-tTAV control were maintained on TET-on media for 5 generations prior to commencing. Thirty flies, 15 male and 15 female, of the same age, from each of the strains were transferred to either TET-On or TET-Off media. Five days after transfer, adult flies were removed and 10 adult flies, 5 male & 5 female, were frozen at -80°C. Ten larvae from each of these matings were collected at the late second instar stage, the last life stage normally seen prior to lethality, and frozen at -80°C. Three biological replicates were produced for each combination of strain, life-stage, and media. RNA was prepared from frozen samples using Trizol and DNAse was treated using a PureLink RNA Mini Kit (Invitrogen). Microarray experiments employed Agilent Drosophila Gene Expression Microarrays 4x44K and were scanned on an Agilent G2505C scanner (Agilent Technologies). Data collection was divided into two separate experiments. A pilot experiment for strain 102D consisting of two life stages in two conditions each with three biological replicates – a total of 12 samples. The remaining four strains were run as a separate experiment with a total of 48 samples. For each experiment, sample chip position was randomized to avoid genotype- and treatment-specific batch effects.
2017-12-11 | E-MTAB-6332 | biostudies-arrayexpress
Project description:Phospholipase C gamma 1 (PLC-γ1) occupies a critically important position in the T cell signaling pathway. While its functions as a regulator of both Ca2+ signaling and PKC-family kinases are well characterized, PLC-γ1’s role in the regulation of early T cell receptor signaling events is incomplete. Activation of the T cell receptor leads to the formation of a signalosome complex between SLP-76, LAT, PLC-γ1, Itk, and Vav1. Recent studies have revealed the existence of both positive and negative feedback pathways from components of the signalosome complex to the apical kinase in the pathway, Lck. To determine the role, if any, of PLC-γ1 in these feedback networks, we performed a quantitative phosphoproteomic analysis of the PLC-γ1-deficient T cells. These data revealed a previously unappreciated role for PLC-γ1 in the positive regulation of Zap-70 and T cell receptor tyrosine phosphorylation. Conversely, PLC-γ1 negatively regulated the phosphorylation of signalosome associated proteins including previously established Lck substrate phosphorylation sites within this complex. While the positive and negative regulatory phosphorylation sites on Lck were largely unchanged, Tyr192 phosphorylation was elevated in Jgamma1. The data supports a model wherein Lck’s targeting, but not its kinase activity is altered by PLC-γ1, possibly through Lck Tyr192 phosphorylation.
2017-06-28 | PXD005165 | Pride