Age-dependent pancreatic gene regulation reveals mechanisms governing human β-cell function
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ABSTRACT:
PROVIDER: PRJNA315900 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR1299320_1.fastq.gz | Fastqsanger.gz | |||
| SRR1299320_2.fastq.gz | Fastqsanger.gz | |||
| SRR1299330_1.fastq.gz | Fastqsanger.gz | |||
| SRR1299330_2.fastq.gz | Fastqsanger.gz | |||
| SRR1299340_1.fastq.gz | Fastqsanger.gz |
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Project description:Pancreatic β-cells are responsible for production and secretion of insulin in response to increasing blood glucose levels. Therefore, defects in pancreatic β-cell function lead to hyperglycemia and diabetes mellitus. Understanding the molecular mechanisms governing β cell function is crucial for development of novel treatment strategies for this disease. The aim of this project was to investigate the role of Cnot3, part of CCR4-NOT complex, major deadenylase complex in mammals, in pancreatic β cell function. Cnot3βKO islets display decreased expression of key regulators of β cell maturation and function. Moreover, they show an increase of progenitor cell markers, β cell-disallowed genes and genes relevant to altered β cell function. Cnot3βKO islets exhibit altered deadenylation and increased mRNA stability, partly accounting for the increase of those genes. Together, these data reveal that CNOT3-mediated mRNA deadenylation and decay constitute previously unsuspected post-transcriptional mechanisms essential for β cell identity.
2020-08-31 | PXD018403 | Pride
Project description:Intensive efforts are focused on identifying regulators of human pancreatic islet cell growth and maturation to accelerate development of therapies for diabetes. After birth, islet cell growth and function are dynamically regulated; however, establishing these age-dependent changes in humans has been challenging. Here, we describe a multimodal strategy for isolating pancreatic endocrine and exocrine cells from children and adults to identify age-dependent gene expression and chromatin changes on a genomic scale. These profiles revealed distinct proliferative and functional states of islet α cells or β cells and histone modifications underlying age-dependent gene expression changes. Expression of SIX2 and SIX3, transcription factors without prior known functions in the pancreas and linked to fasting hyperglycemia risk, increased with age specifically in human islet β cells. SIX2 and SIX3 were sufficient to enhance insulin content or secretion in immature β cells. Our work provides a unique resource to study human-specific regulators of islet cell maturation and function.
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Project description:Aging is associated with fundamental changes in pancreatic β-cell physiology; yet, the mechanisms that drive these age-related changes are poorly understood. We performed comprehensive proteomic profiling of pancreatic islets from adolescent and old mice. The analysis revealed striking differences in abundance of enzymes controlling glucose metabolism not reflected at the transcript level. We show that these changes in protein abundance are associated with increased activity of the amplifying pathway of insulin secretion. The amplifying pathway stimulates insulin secretion through coupling factors produced during glucose metabolism. Nutrient tracing and targeted metabolomics demonstrate accelerated accumulation of glucose-derived metabolites and coupling factors in aged islets, indicating that age-related changes in glucose metabolism contribute to the improved response of β-cells to glucose with age. Together, our study provides the first in-depth characterization of changes in the islet proteome during aging and establishes metabolic rewiring as an important mechanism for age-associated changes in β-cell function.
2018-12-03 | GSE104591 | GEO
Project description:Individual organisms age at different rates, however, it remains unclear how aging alters the properties of individual cells. Here we show that zebrafish pancreatic beta-cells exhibit heterogeneity in both gene expression and proliferation with age. Individual beta-cells show marked variability in transcripts involved in endoplasmic reticulum stress, inhibition of growth factor signaling and inflammation, including NF-kB signaling. Using a reporter line, we show that NF-kB signaling is indeed activated heterogeneously with age. Notably, beta-cells with higher NF-kB activity proliferate less compared to neighbors with lower activity. Furthermore, NF-kB-signalinghigh beta-cells from younger islets upregulate socs2, a gene naturally expressed in beta-cells from older islets. In turn, socs2 can inhibit proliferation cell-autonomously. NF-kB activation correlates with the recruitment of tnfα-expressing immune cells, pointing towards a role for the islet microenvironment in this activity. We propose that aging is heterogeneous across individual beta-cells and identify NF-kB signaling as a marker of heterogeneity.
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Project description:Glucose plays a key role in shaping pancreatic β cell function. Thus, deciphering the mechanisms by which this nutrient stimulates β cells holds therapeutic promise for combating β cell failure in type 2 diabetes (T2D). β cells respond to hyperglycemia in part by rewiring their mRNA metabolism, yet the factors governing these changes remain poorly understood. Here, we interrogate the transcriptomes of control β cells and mutant β cells lacking the RNA binding protein PCBP incubated with low or high glucose for 72 hours.
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Project description:This SuperSeries is composed of the SubSeries listed below.
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Project description:Objective: Disturbances in NAD+ metabolism have been described as a hallmark for multiple metabolic and age-related diseases, including type 2 diabetes. While alterations in pancreatic -cell function are critical determinants of whole-body glucose homeostasis, the role of NAD+ metabolism in the endocrine pancreas remains poorly explored. Here, we aimed to evaluate the role of nicotinamide riboside (NR) metabolism in maintaining NAD+ levels and pancreatic -cell function in pathophysiological conditions. Methods: Whole body and pancreatic -cell-specific NRK1 knockout (KO) mice were metabolically characterized in situations of high-fat feeding and aging. We also analyzed pancreatic -cell function and gene expression. Results: We first demonstrate that NRK1, the essential enzyme for the utilization of NR, is substantially expressed in pancreatic -cells. While NR treatment did not alter glucose-stimulated insulin secretion in pancreatic islets from young healthy mice, NRK1 knockout mice displayed glucose intolerance and compromised -cells response to a glucose challenge upon high-fat feeding or aging. Interestingly, β cells dysfunction stemmed from the functional failure of other organs, such as liver and kidney, and the associated changes in circulating peptides and hormones, as mice lacking NRK1 exclusively in β-cells did not show altered glucose homeostasis. Conclusions: This work unveils a new physiological role for NR metabolism in the maintenance of glucose tolerance and pancreatic -cell function in high-fat feeding or aging conditions.
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Project description:TMT-labeled phosphoproteome data of mouse pancreatic beta cell
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Project description:Islet β-cells from newborn mammals need a maturation process to become mature functional beta cells. The detailed molecular mechanisms were not completely understood. This study was designed to reveal the dynamic gene expression changes during pancreatic beta-cell maturation in postnatal mice. We also want to understand how genetic mutations that impair beta-cell function change the genetic networks involved in the beta-cell maturation process. For these aims, pancreatic beta cells were isolated at P1 islets based on the expression of a MipeGFP transgene in a genetic background with pancreatic specific inactivation of Myt1, Myt1L, and St18 (denoted as MytDelpanc; MipeGFP).
2018-04-01 | E-MTAB-6615 | biostudies-arrayexpress
Project description:Glis3 is expressed in pancreatic beta and PP cells. To identify down stream target genes of Glis3, we performed microarray analysis using pancreas total RNAs from 1 week-old WT and Glis3KO2 mice. insulin and pancreatic polypeptide (Ppy) was significantly decreased together with several other β cell markers, Glut2 and MafA by microarray analysis. Immunohistochemistry, QRT-PCR, and transmission electron microscopy indicated that postnatal Glis3KO2 pancreas still contains a large population of β cells that express Pdx-1, Nkx6.1, and Isl-1; however, insulin production and secretory granules were greatly reduced in these cells. In addition, chromogranin A (ChgA) and Urocortin 3, which are associated with mature β cells, was dramatically decreased in Glis3KO2 pancreas. These observations suggest that Glis3 plays a critical role in the maturation of pancreatic β cell phenotype. Pancreatic total RNAs were purified from 4 WT and 4 Glis3KO2 at 1 week old age. Then the samples were applied to Agilent mouse genome chip.
2016-07-01 | E-GEOD-67238 | biostudies-arrayexpress