Induction of alpha cell-restricted Gc in dedifferentiating beta cells contributes to stress-induced beta-cell dysfunction [ChIP-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA542265 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9040230.fastq.gz | Fastqsanger.gz | |||
| SRR9040231.fastq.gz | Fastqsanger.gz | |||
| SRR9040232.fastq.gz | Fastqsanger.gz | |||
| SRR9040233.fastq.gz | Fastqsanger.gz | |||
| SRR9040234.fastq.gz | Fastqsanger.gz |
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Project description:Induction of alpha cell-restricted Gc in dedifferentiating beta cells contributes to stress-induced beta-cell dysfunction [RNA-seq]
| PRJNA542266 | ENA
Project description:To identify effector genes of pancreatic beta cell dedifferentiation and dysfunction, we performed RNA expression in beta cells sorted from mice with multiparity-induced diabetes.
2019-05-30 | GSE130997 | GEO
Project description:To identify effector genes of pancreatic beta cell dedifferentiation and dysfunction, we integrated analyses of histone methylation as a surrogate of gene activation status and RNA expression in beta cells sorted from mice with multiparity-induced diabetes.
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Project description:Diabetic β cell failure is associated with β cell dedifferentiation. To identify effector genes of dedifferentiation, we integrated analyses of histone methylation as a surrogate of gene activation status and RNA expression in β cells sorted from mice with multiparity-induced diabetes. Interestingly, only a narrow subset of genes demonstrated concordant changes to histone methylation and RNA levels in dedifferentiating β cells. Notable among them was the α cell signature gene Gc, encoding a vitamin D-binding protein. While diabetes was associated with Gc induction, Gc-deficient islets did not induce β cell dedifferentiation markers and maintained normal ex vivo insulin secretion in the face of metabolic challenge. Moreover, Gc-deficient mice exhibited a more robust insulin secretory response than normal controls during hyperglycemic clamps. The data are consistent with a functional role of Gc activation in β cell dysfunction, and indicate that multiparity-induced diabetes is associated with altered β cell fate.
| S-EPMC6629129 | biostudies-literature
Project description:Objective: Although glucagon-secreting α-cells and insulin-secreting β-cells have opposing functions in regulating plasma glucose levels, the two cell types share a common developmental origin and have overlaps in their transcriptome and epigenome profiles. Notably, destruction of one of these cell populations can stimulate repopulation via transdifferentiation of the other cell type, at least in mice, suggesting plasticity between these cell fates. Furthermore, dysfunction of both α- and β-cells contributes to the pathophysiology of type 1 and type 2 diabetes, and β-cell de-differentiation has been proposed to contribute to type 2 diabetes. Our objective was to delineate the molecular properties that maintain islet cell type specification yet allow for cellular plasticity. We hypothesized that correlating cell type-specific transcriptomes with an atlas of open chromatin will identify novel genes and transcriptional regulatory elements such as enhancers involved in α- and β-cell specification and plasticity. Methods: We sorted human a- and b-cells and performed the â??Assay for Transposase-Accessible Chromatin with high throughput sequencingâ?? (ATAC-seq) and mRNA-seq, followed by integrative analysis to identify cell type-selective gene regulatory regions. Results: We identified numerous transcripts with either α-cell- or β-cell-selective expression and discovered the cell type-selective open chromatin regions that correlate with these gene activation patterns. We confirmed cell type-selective expression on the protein level for two of the top hits from our screen. The â??group specific proteinâ?? (GC; or vitamin D binding protein) was restricted to a-cells, while CHODL (chondrolectin) immunoreactivity was only present in b-cells. Furthermore, α-cell- and β-cell-selective ATAC-seq peaks were identified to overlap with known binding sites for islet transcription factors, as well as with common single nucleotide polymorphisms (SNPs) previously identified as risk loci for type 2 diabetes. Conclusions: We have determined the genetic landscape of human α- and β-cells based on chromatin accessibility and transcript levels, which allowed for detection of novel α- and β-cell signature genes not previously known to be expressed in islets. Using fine-mapping of open chromatin, we have identified thousands of potential cis-regulatory elements that operate in an endocrine cell type-specific fashion. ATAC-seq on 3 human alpha cell samples, 3 human beta cell samples, and 2 human acinar cell samples. RNA-seq on 7 human alpha cell samples and 8 human beta cell samples.
2015-12-23 | E-GEOD-76268 | biostudies-arrayexpress
Project description:Objective: Although glucagon-secreting α-cells and insulin-secreting β-cells have opposing functions in regulating plasma glucose levels, the two cell types share a common developmental origin and have overlaps in their transcriptome and epigenome profiles. Notably, destruction of one of these cell populations can stimulate repopulation via transdifferentiation of the other cell type, at least in mice, suggesting plasticity between these cell fates. Furthermore, dysfunction of both α- and β-cells contributes to the pathophysiology of type 1 and type 2 diabetes, and β-cell de-differentiation has been proposed to contribute to type 2 diabetes. Our objective was to delineate the molecular properties that maintain islet cell type specification yet allow for cellular plasticity. We hypothesized that correlating cell type-specific transcriptomes with an atlas of open chromatin will identify novel genes and transcriptional regulatory elements such as enhancers involved in α- and β-cell specification and plasticity. Methods: We sorted human a- and b-cells and performed the “Assay for Transposase-Accessible Chromatin with high throughput sequencing” (ATAC-seq) and mRNA-seq, followed by integrative analysis to identify cell type-selective gene regulatory regions. Results: We identified numerous transcripts with either α-cell- or β-cell-selective expression and discovered the cell type-selective open chromatin regions that correlate with these gene activation patterns. We confirmed cell type-selective expression on the protein level for two of the top hits from our screen. The “group specific protein” (GC; or vitamin D binding protein) was restricted to a-cells, while CHODL (chondrolectin) immunoreactivity was only present in b-cells. Furthermore, α-cell- and β-cell-selective ATAC-seq peaks were identified to overlap with known binding sites for islet transcription factors, as well as with common single nucleotide polymorphisms (SNPs) previously identified as risk loci for type 2 diabetes. Conclusions: We have determined the genetic landscape of human α- and β-cells based on chromatin accessibility and transcript levels, which allowed for detection of novel α- and β-cell signature genes not previously known to be expressed in islets. Using fine-mapping of open chromatin, we have identified thousands of potential cis-regulatory elements that operate in an endocrine cell type-specific fashion.
2015-12-23 | GSE76268 | GEO
Project description:Interferon (IFN)-α is the earliest cytokine signature observed in individuals at risk for type 1 diabetes (T1D), but its effect on the repertoire of HLA Class I (HLA-I)-bound peptides presented by pancreatic β-cells is unknown. Using immunopeptidomics, we characterized the peptide/HLA-I presentation in in-vitro resting and IFN-α-exposed β-cells. IFN-α increased HLA-I expression and peptide presentation, including neo-sequences derived from alternative mRNA splicing, post-translational modifications - notably glutathionylation - and protein cis-splicing. This antigenic landscape relied on processing by both the constitutive and immune proteasome. The resting β-cell immunopeptidome was dominated by HLA-A-restricted ligands. However, IFN-α only marginally upregulated HLA-A and largely favored HLA-B, translating into a major increase in HLA-B-restricted peptides and into an increased activation of HLA-B-restricted vs. HLA-A-restricted CD8+ T-cells. A preferential HLA-B hyper-expression was also observed in the islets of T1D vs. non-diabetic donors, and islet-infiltrating CD8+ T-cells from T1D donors were reactive to some HLA-B-restricted granule peptides. Thus, the inflammatory milieu of insulitis may skew the autoimmune response toward epitopes presented by HLA-B, hence recruiting a distinct T-cell repertoire that may be relevant to T1D pathogenesis.
2025-01-08 | PXD045265 | Pride
Project description:Rodent models are widely used to study diabetes. Yet, significant gaps remain in our understanding of mouse islet physiology that reduce their accuracy as a model for human islet disease. We generated comprehensive transcriptomes of mouse beta and alpha cells using a novel bitransgenic mouse model generated for this purpose. This enables systematic comparison across thousands of genes between the two major endocrine cell types of the islets of Langerhans whose principal hormones are of cardinal importance for glucose homeostasis. Our data leveraged against similar data for human beta cells reveal a core common beta cell transcriptome of 9900+ genes and marked differences in the repertoire of receptors and long non-coding RNAs between mouse and human beta cells. The comprehensive comparison of the (dis)similarities between mouse and human beta cells represents an invaluable resource to boost the effectiveness by which rodent models offer guidance in finding cures for human diabetes. FACS purified alpha and beta cells from the same islets. Islets were isolated from bitransgenic offspring of a cross between mIns1-H2b-mCherry and S100b-eGFP transgenic reporter mice that mark beta and alpha cells, respectively. Islets from two replicate groups of 10 or 11 animals were pooled by sex to obtain sufficient material. Pooled islets were dissociated, sorted and collect in Trizol for RNA isolation and library construction.
2014-09-16 | E-GEOD-54973 | biostudies-arrayexpress