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Phenothiazine Neuroleptics Signal To The Human Insulin Promoter As Revealed By A Novel Human b-Cell Line Based Screen

ABSTRACT: (original Title) Phenothiazine Neuroleptics Signal To The Human Insulin Promoter As Revealed By A Novel Human b-Cell Line Based High-Throughput Screen. To address the current deficiency in human beta-cell models, we have developed a cell line from human islets in which the expression of insulin and other beta-cell restricted genes are modulated by an inducible form of the bHLH transcription factor E47. In an effort to probe the global pattern of gene expression in T6PNE in an unbiased fashion, oligonucleotide microarray analysis was performed on T6PNE in the presence and absence of E47 induction and compared against human islets. Our analysis reveals that T6PNE express a substantial percentage of the b-cell specific geneset, and that this is further enhanced by the induction of E47. This cell line, T6PNE, was then screened against a library of known drugs for those that increase insulin promoter activity. Interestingly, members of the phenothiazine class of neuroleptics increased insulin gene expression upon short term exposure. Chronic treatment, however, resulted in suppression of insulin promoter activity, consistent with the effect of phenothiazines observed clinically to induce diabetes in chronically treated patients. In addition to providing insights into previously unrecognized targets and mechanisms of action of phenothiazines, the novel cell line described here provides a broadly applicable platform for mining new molecular drug targets and central regulators of beta-cell differentiated function.

ORGANISM(S): Homo sapiens

PROVIDER: GSE18821 | GEO | 2010/08/07

SECONDARY ACCESSION(S): PRJNA121687

REPOSITORIES: GEO

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Phenothiazine Neuroleptics Signal To The Human Insulin Promoter As Revealed By A Novel Human b-Cell Line Based Screen

Project description:(original Title) Phenothiazine Neuroleptics Signal To The Human Insulin Promoter As Revealed By A Novel Human b-Cell Line Based High-Throughput Screen. To address the current deficiency in human beta-cell models, we have developed a cell line from human islets in which the expression of insulin and other beta-cell restricted genes are modulated by an inducible form of the bHLH transcription factor E47. In an effort to probe the global pattern of gene expression in T6PNE in an unbiased fashion, oligonucleotide microarray analysis was performed on T6PNE in the presence and absence of E47 induction and compared against human islets. Our analysis reveals that T6PNE express a substantial percentage of the b-cell specific geneset, and that this is further enhanced by the induction of E47. This cell line, T6PNE, was then screened against a library of known drugs for those that increase insulin promoter activity. Interestingly, members of the phenothiazine class of neuroleptics increased insulin gene expression upon short term exposure. Chronic treatment, however, resulted in suppression of insulin promoter activity, consistent with the effect of phenothiazines observed clinically to induce diabetes in chronically treated patients. In addition to providing insights into previously unrecognized targets and mechanisms of action of phenothiazines, the novel cell line described here provides a broadly applicable platform for mining new molecular drug targets and central regulators of beta-cell differentiated function. Gene expression studies in: Three human islet samples; Five T6PNE samples; Seven T6PNE induced with E47.

2010-08-06 | E-GEOD-18821 | biostudies-arrayexpress

Expression data comparing adult human islets to human embryonic stem cell-derived insulin-positive and insulin-negative cells

Project description:The study was completed to compare expression profiles of primary human beta cells (in the form of adult human islets), to the expression profile of hESC-derived beta-like cells. A HES3 line modified by homologous recombination to express GFP under the insulin promoter allowed us to FACS sort the hESC-derived cells into purified insulin-positive (presumably beta-like cells), and insulin-negative populations. Expression profile of adult human islets from cadaveric donors is compared to insulin-positive and insulin-negative populations of hESC-derived beta-like cells

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Expression data comparing adult human islets to human embryonic stem cell-derived insulin-positive and insulin-negative cells

2012-09-09 | GSE40709 | GEO

Epigenomic plasticity enables human pancreatic alpha to beta cell reprogramming

Project description:Insulin-secreting β cells and glucagon-secreting α cells maintain physiological blood glucose levels, and their malfunction drives diabetes development. Using ChIP sequencing and RNA sequencing analysis, we determined the epigenetic and transcriptional landscape of human pancreatic α, β, and exocrine cells. We found that, compared with exocrine and β cells, differentiated α cells exhibited many more genes bivalently marked by the activating H3K4me3 and repressing H3K27me3 histone modifications. This was particularly true for β cell signature genes involved in transcriptional regulation. Remarkably, thousands of these genes were in a monovalent state in β cells, carrying only the activating or repressing mark. Our epigenomic findings suggested that α to β cell reprogramming could be promoted by manipulating the histone methylation signature of human pancreatic islets. Indeed, we show that treatment of cultured pancreatic islets with a histone methyltransferase inhibitor leads to colocalization of both glucagon and insulin and glucagon and insulin promoter factor 1 (PDX1) in human islets and colocalization of both glucagon and insulin in mouse islets. Thus, mammalian pancreatic islet cells display cell-type–specific epigenomic plasticity, suggesting that epigenomic manipulation could provide a path to cell reprogramming and novel cell replacement-based therapies for diabetes. Pancreatic islets were collected post-mortem from 6 human donors and subjected to FACS to separate populations of alpha, beta, and exocrine cells. Depending on the availability of resulting material, sorted islet cell populations were used for H3K4me3, H3K27me3 ChIP-seq, or RNA-seq analysis. All ChIP-seq samples have a corresponding input from the same sample.

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2024-01-17 | PXD045366 | Pride

Epigenomic plasticity enables human pancreatic alpha to beta cell reprogramming

2013-08-28 | GSE50386 | GEO

Epigenetic regulation of the MEG3-DLK1 microRNA cluster in human Type 2 diabetic islets

Project description:Type 2 diabetes mellitus (T2DM) is a complex disease characterized by the inability of the insulin-producing β-cells in the endocrine pancreas to overcome insulin resistance in peripheral tissues. To determine if microRNAs are involved in the pathogenesis of human T2DM, we sequenced the small RNAs of human islets from diabetic and non-diabetic organ donors. We identified a cluster of miRNAs in an imprinted locus on human chromosome 14q32 that is highly and specifically expressed in human β-cells and dramatically down-regulated in islets from T2DM organ donors. The down-regulation of this locus strongly correlates with hyper-methylation of its promoter. Using HITS-CLIP for the essential RISC-component Argonaute, we identified disease-relevant targets of the chromosome 14q32 microRNAs, such as IAPP and TP53INP1 that cause increased β-cell apoptosis upon over-expression in human islets. Our results support a role for microRNAs and their epigenetic control by DNA methylation in the pathogenesis of T2DM. Identification of miRNA-target interaction in human islets using HITS-CLIP, one mRNA library and one miRNA library

2013-11-22 | E-GEOD-51924 | biostudies-arrayexpress

Homo sapiens

Project description:Phenothiazine Neuroleptics Signal To The Human Insulin Promoter As Revealed By A Novel Human b-Cell Line Based Screen

| PRJNA121687 | ENA

Regulated and adaptive in vivo insulin secretion from islets only containing β-cells

Project description:The activity of pancreatic islets’ insulin-producing β-cells is closely regulated by systemic cues and, locally, by adjacent islet hormone-producing “non-β-cells” (namely α-, δ- and γ-cells). Still, it is unclear whether the presence of the non-β-cells is a requirement for accurate insulin secretion. Here, we generated and studied a mouse model in which adult islets are exclusively composed of β-cells, and human pseudoislets containing only primary β-cells. Mice lacking non-β-cells had optimal blood glucose regulation. They exhibited enhanced glucose tolerance, insulin sensitivity and restricted body weight gain under high-fat diet. The insulin secretion dynamics in islets composed of only β-cells was like in intact islets, both in homeostatic conditions and upon extreme insulin demand. Similarly, human β-cell pseudoislets retained the glucose-regulated mitochondrial respiration, insulin secretion and exendin-4 responses of human islets comprising all four cell types. Together, the findings indicate that non-β-cells are dispensable for blood glucose homeostasis and β-cell function. This is particularly relevant in diabetes, where non-β-cells become dysfunctional and worsen the disease’s pathophysiology. These results support efforts aimed at developing diabetes treatments by generating β-like cell clusters devoid of non-β-cells, as for example from human embryonic stem cells and/or by in situ conversion of non-β-cells into insulin producers.

2024-07-19 | GSE226479 | GEO

Mapping of INS promoter interactions reveals its role in long-range regulation of SYT8 transcription

Project description:Insulin (INS) synthesis and secretion from pancreatic β cells are tightly regulated; their deregulation causes diabetes. Here we map INS-associated loci in human pancreatic islets by 4C and 3C techniques and show that the INS gene physically interacts with the SYT8 gene, located over 300 kb away. This interaction is elevated by glucose and accompanied by increases in SYT8 expression. Inactivation of the INS promoter by promoter-targeting siRNA reduces SYT8 gene expression. SYT8-INS interaction and SYT8 transcription are attenuated by CTCF depletion. Furthermore, SYT8 knockdown decreases insulin secretion in islets. These results reveal a non-redundant role for SYT8 in insulin secretion and indicate that the INS promoter acts from a distance to stimulate SYT8 transcription. This suggests a function for the INS promoter in coordinating insulin transcription and secretion through long-range regulation of SYT8 expression in human islets.

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