Integrator of Stress Responses Calmodulin Binding Transcription Activator 1 (Camta1) Regulates miR-212/miR-132 Expression and Insulin Secretion

Mollet, Inês G.; Malm, Helena; Wendt, Anna; Orho‐Melander, Marju; Eliasson, Lena

doi:10.1074/jbc.m116.716860

Cited by 27 publications

(24 citation statements)

References 55 publications

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“…We hypothesized that this was due to a perturbed transcriptional regulation and we therefore performed promoter analysis to find out DNA sequence motifs common to the upregulated miRNAs. However we only found common DNA sequence motif in the promoter region of two other upregulated miRNAs in the GK rat islets, miR-132 and miR-21234. In that study our group showed putative transcription factor binding sites for Calmodulin Binding Transcription Activator 1 (Camta1) and NK2 homeobox protein, Nkx2-2.…”

Section: Discussionmentioning

confidence: 69%

Elevated miR-130a/miR130b/miR-152 expression reduces intracellular ATP levels in the pancreatic beta cell

Ofori

Salunkhe

Bagge

et al. 2017

Sci Rep

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MicroRNAs have emerged as important players of gene regulation with significant impact in diverse disease processes. In type-2 diabetes, in which impaired insulin secretion is a major factor in disease progression, dysregulated microRNA expression in the insulin-secreting pancreatic beta cell has been widely-implicated. Here, we show that miR-130a-3p, miR-130b-3p, and miR-152-3p levels are elevated in the pancreatic islets of hyperglycaemic donors, corroborating previous findings about their upregulation in the islets of type-2 diabetes model Goto-Kakizaki rats. We demonstrated negative regulatory effects of the three microRNAs on pyruvate dehydrogenase E1 alpha (PDHA1) and on glucokinase (GCK) proteins, which are both involved in ATP production. Consequently, we found both proteins to be downregulated in the Goto-Kakizaki rat islets, while GCK mRNA expression showed reduced trend in the islets of type-2 diabetes donors. Overexpression of any of the three microRNAs in the insulin-secreting INS-1 832/13 cell line resulted in altered dynamics of intracellular ATP/ADP ratio ultimately perturbing fundamental ATP-requiring beta cell processes such as glucose-stimulated insulin secretion, insulin biosynthesis and processing. The data further strengthen the wide-ranging influence of microRNAs in pancreatic beta cell function, and hence their potential as therapeutic targets in type-2 diabetes.

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Section: Discussionmentioning

confidence: 69%

Elevated miR-130a/miR130b/miR-152 expression reduces intracellular ATP levels in the pancreatic beta cell

Ofori

Salunkhe

Bagge

et al. 2017

Sci Rep

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“…We have determined that NKX2.2 expression is downregulated more than 5-fold (P adjusted < 1.19 × 10 -7 ) in db/db mouse islets, and a recent study demonstrated that NKX2.2 expression was reduced in the diabetic Goto-Kakizaki rat model (41). Reduced NKX2.2 expression has also been reported in primate models of diabetes induced by a high-fat/sugar diet (42).…”

Section: Discussionmentioning

confidence: 90%

Pancreatic β cell identity requires continual repression of non–β cell programs

Gutiérrez¹,

Bender²,

Cirulli³

et al. 2016

Journal of Clinical Investigation

105

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from alternative islet cell fates. Furthermore, β cells appeared to transdifferentiate to acquire other non-β cell endocrine identities. Deletion of Nkx2.2 in fully differentiated adult β cells also resulted in the very rapid onset of diabetes, and the islets of these mice were also characterized by a loss of β cell identity and the acquisition of δ cell characteristics, confirming the importance of NKX2.2 ration and/or function, we generated mouse models that allowed constitutive and inducible deletion of the Nkx2.2 gene. Disruption of Nkx2.2 in maturing β cells resulted in the rapid development of diabetes, with a significant decrease in insulin expression and content. Strikingly, the loss of genes associated with β cell identity and function was accompanied by increased expression of genes ΔBeta compared with control mice at 4 weeks of age. The white boxes indicate regions of the islet that are shown in higher magnification in E and F. (G) Ad libitum blood glucose levels in 2-week-old male Nkx2.2ΔBeta mice compared with controls (n = 3-16), in 3-week-old mice (n = 5-22), and in 11-week-old mice (n = 6-18). **P ≤ 0.01, ***P ≤ 0.001; 2-tailed Student's t test. Each control genotype was examined separately to ensure that the individual Cre and floxed alleles did not cause metabolic phenotypes. (H) Higher fasting blood glucose levels are evident in 11-week-old Nkx2.2ΔBeta mice compared with controls (3-week-old mice: n = 6-23; 11-week-old mice: n = 8-21). *P ≤ 0.05; 2-tailed Student's t test. (I) Glucose intolerance is observed in Nkx2.2ΔBeta male mice compared with controls at 3 weeks of age (n = 6-23). *P ≤ 0.05, ***P ≤ 0.001; 2-tailed Student's t test. (J) Glucose intolerance becomes more severe at 11 weeks of age in Nkx2.2ΔBeta male mice compared with control mice (n = 8-21). *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001; 2-tailed Student's t test.

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“…We observed a trans -association between rs602662 and the downregulation of CAMTA1 only within the pancreas. The CAMTA1 gene product has been demonstrated to play an integral role in the regulation of microRNA profiles (i.e., miR-212/miR-132) and beta cell function, with the differential expression of transcript levels implicated in the pathogenesis of diabetes ( Mollet et al, 2016 ). Collectively our results are consistent with trans - and cis -regulatory elements, located at or surrounding T1D eQTL-SNPs, acting to control a previously unrecognized network of genes that: (a) modulate the immune response; and (b) affect pancreatic beta cell function and survival.…”

Section: Discussionmentioning

confidence: 99%

Type 1 Diabetes Mellitus-Associated Genetic Variants Contribute to Overlapping Immune Regulatory Networks

et al. 2018

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Type 1 diabetes (T1D) is a chronic metabolic disorder characterized by the autoimmune destruction of insulin-producing pancreatic islet beta cells in genetically predisposed individuals. Genome-wide association studies (GWAS) have identified over 60 risk regions across the human genome, marked by single nucleotide polymorphisms (SNPs), which confer genetic predisposition to T1D. There is increasing evidence that disease-associated SNPs can alter gene expression through spatial interactions that involve distal loci, in a tissue- and development-specific manner. Here, we used three-dimensional (3D) genome organization data to identify genes that physically co-localized with DNA regions that contained T1D-associated SNPs in the nucleus. Analysis of these SNP-gene pairs using the Genotype-Tissue Expression database identified a subset of SNPs that significantly affected gene expression. We identified 246 spatially regulated genes including HLA-DRB1, LAT, MICA, BTN3A2, CTLA4, CD226, NOTCH1, TRIM26, PTEN, TYK2, CTSH, and FLRT3, which exhibit tissue-specific effects in multiple tissues. We observed that the T1D-associated variants interconnect through networks that form part of the immune regulatory pathways, including immune-cell activation, cytokine signaling, and programmed cell death protein-1 (PD-1). Our results implicate T1D-associated variants in tissue and cell-type specific regulatory networks that contribute to pancreatic beta cell inflammation and destruction, adaptive immune signaling, and immune-cell proliferation and activation. A number of other regulatory changes we identified are not typically considered to be central to the pathology of T1D. Collectively, our data represent a novel resource for the hypothesis-driven development of diagnostic, prognostic, and therapeutic interventions in T1D.

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Integrator of Stress Responses Calmodulin Binding Transcription Activator 1 (Camta1) Regulates miR-212/miR-132 Expression and Insulin Secretion

Cited by 27 publications

References 55 publications

Elevated miR-130a/miR130b/miR-152 expression reduces intracellular ATP levels in the pancreatic beta cell

Elevated miR-130a/miR130b/miR-152 expression reduces intracellular ATP levels in the pancreatic beta cell

Pancreatic β cell identity requires continual repression of non–β cell programs

Type 1 Diabetes Mellitus-Associated Genetic Variants Contribute to Overlapping Immune Regulatory Networks

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