M6A RIP-seq for Cytokine-treated Islets and Beta-cells or T1D Islets
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA949172 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23979100_1.fastq.gz | Fastqsanger.gz | |||
| SRR23979100_2.fastq.gz | Fastqsanger.gz | |||
| SRR23979200_1.fastq.gz | Fastqsanger.gz | |||
| SRR23979200_2.fastq.gz | Fastqsanger.gz | |||
| SRR23979101_1.fastq.gz | Fastqsanger.gz |
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Project description:Type 1 Diabetes (T1D) is characterized by autoimmune-mediated destruction of insulin-producing beta-cells. Recent research has focused on the role of the innate immune system in initiating this process. To investigate this further, we used m6A-profiling of human islets from non-diabetic individuals and the human beta-cell line EndoC-bH1 treated with PBS or interleukin 1 beta and interferon alpha, as well as established T1D patients. Our findings reveal that N6-Methyladenosine (m6A) is a mechanism that helps protect beta-cells by accelerating the decay of mRNA from the 2'-5'-oligoadenylate synthetase (OAS) genes, which controls the antiviral innate immune response at the onset of T1D. These results provide insight into the adaptive safeguarding mechanisms of beta-cells and the role of m6A in T1D development, highlighting potential targets for therapeutic interventions.
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Project description:Our current understanding of the pathogenesis of T1D arose in large part from studies using the non-obese diabetic (NOD) mouse model of type 1 diabetes (T1D). Of concern, therapeutic interventions shown to significantly dampen or even reverse disease in mouse models have not successfully translated into interventions in human T1D. The present study addresses this disconnect in research translation by directly analyzing human donor islets from individuals with T1D, aiming to provide insight into disease mechanisms and identify potential target pathways for therapeutic intervention. We obtained human islets from a young individual with short-duration T1D, an older individual with long-duration T1D and three non-diabetic donors, and performed unbiased functional genomic analysis by high depth RNA sequencing on these unique cases. This analysis identified several inflammatory pathways upregulated in short-duration disease, which surprisingly included many components of innate immunity. Subsequent manipulation of one of these pathways/factors in NOD mice resulted in a significant reduction in diabetes progression when inhibition occurred early in disease progression. Taken together our data demonstrates that the direct analysis of human islets is essential for identifying relevant and promising novel targets for translation into effective therapeutic interventions for human T1D.
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Project description:Biomarkers capable of monitoring β cell stress during the evolution of type 1 diabetes (T1D) are currently lacking. MicroRNAs (miRNAs) are a class of small non-coding RNAs ~22 nucleotides in length that modulate gene expression by binding to the 3’untranslated region of target mRNAs. Given their stability in biological fluids and enrichment in cell-derived EVs, we hypothesized that miRNAs from human islet and islet-derived EVs could identify β-cell stress/death and be leveraged in T1D biomarker strategies. To test this, human islets were obtained from 10 cadaveric donors (5 male/5 female) and treated with or without cytokines (IL-1β and IFN-γ) for 24 hrs, as an ex vivo model of T1D. Small RNA sequencing was performed and identified 1110 and 890 miRNAs in total and 20 and 14 differentially expressed (DE) miRNAs (fold change≥1.5 and p<0.05) from islets and EVs, respectively. These findings were validated in an independent set of cytokine-treated islets and islet-derived EVs (7M and 5F donors). Interestingly, miRNA expression pattern was strikingly different between male and female donors at baseline and under cytokine stress with < 10% overlap among the DE miRNAs. miR-155-5p and miR-146a-5p were the only two miRNAs that were upregulated in cytokine-treated islets and EVs in both the sexes. Functional enrichment analysis of DE miRNAs identified pathways such as insulin signaling, ER stress and apoptosis. Taken together, these data suggest that miRNA expression patterns change dynamically in both human islets and islet-derived EVs in response to pro-inflammatory cytokine stress. EV miRNAs were largely distinct from those in the islet fraction, suggesting that miRNAs are selectively packaged into EVs in response to extrinsic cues. Finally, these data highlight the importance of considering sex as a biological variable when defining T1D biomarkers.
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Project description:The menin tumor suppressor protein (Men1) is deficient in many endocrine tumors and forms an active complex with MLL family histone methyltransferases. This Men1 complex promotes histone H3 lysine 4 trimethylation at target loci including homeobox genes and cyclin-dependent kinase inhibitor genes. The loss of Men1 may be tumorigenic because it leads to decreased histone H3 lysine 4 trimethylation resulting in expressional changes of specific genes. Reversing tumorigenesis induced by a Men1 deficiency might be achieved by inhibition of histone H3 lysine 4 demethylase Rbp2 (Kdm5a). To this end, pancreatic islets from Men1f|f, Rbp2f|f and Men1f|f Rbp2f|f mice were expression profiled to determine what transcriptional changes induced by a Men1 deficiency are reversed by the loss of Rpb2. Pancreatic islets were isolated from Men1flf RIP-Cre mice, Rbp2flf RIP-Cre mice, Men1flf Rbp2flf RIP-Cre mice and two month old matched control mice. Total mRNA was extracted from islets and expression profiled on microarrays.
2011-07-25 | E-GEOD-26978 | biostudies-arrayexpress
Project description:Purpose: In the early phases of T1D development exposure of β-cells to IFNγ, IL-1β, and TNFα is thought to induce β-cell dysfunction and the expression of chemokines and cytokines. These changes are mediated in part by post-translational histone modifications within cis-regulatory regions. The purpose of this study was to determine if prevention of these epigenetic changes can alter cytokine induced gene expression changes. Methods: Pancreatic islets were isolated from both male and female CD1 mice by collagenase digestion and were picked by hand. Hand-picked islets were cultured for four days with 1.6ng/ml IFNγ, 0.25ng/ml IL-1β and 0.16ng/ml TNFα (cytokine) or were left untreated (nocytokine). For RNA-seq islets were collected and processed for NGS using the Illumina TruSeq library prep kit. Chromatin immunoprecipitation (ChIP) was performed using 3μg of anti-H3K4me1 (Abcam) with islets from at least 10 adult ICR mice (8-10 weeks old) exposed to 1.6ng/ml IFNγ, 0.25ng/ml Il-1β and 0.16ng/ml TNFα for four days. DNA from 4 separate ChIP experiments was pooled for library construction and sequencing using the Illumina platform. Results: Comparison of gene expression levels between untreated and cytokine-treated islets resulted in the identification of 205 genes that showed an IFNγ, Il-1β, and TNFα-induced chromatin state change (from repressed or inactive to H3K4me1 enriched, i.e. the de novo regions), or increased H3K4me1 enrichment, that were associated with genes with up-regulated expression in response to IFNγ, Il-1β, and TNFα, and 111 genes with reduced H3K4me1 and down-regulated expression in response to IFNγ, Il-1β, and TNFα. Conclusions: Our study confirms that exposure of islets to pro-inflammatory cytokines induces the expression of chemokines and that these changes are the result of a switch from an inactive to an active chromatin state. Further we show that disruption of the trithorax group complex inhibits the upregulation of pro-inflammatory gene expression.
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Project description:Patchseq Data of T1D Donor Islets vs ND Matched Controls
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Project description:Through m6A mRNA-profiling, we aim to characterize the m6A mRNA changes in pancreatic islets between Wtapflox/flox and Wtap-βKO mice.
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