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Journal articleMiguel-Escalada I, Bonàs-Guarch S, Cebola I, et al., 2019,
Human pancreatic islet three-dimensional chromatin architecture provides insights into the genetics of type 2 diabetes
, Nature Genetics, Vol: 51, Pages: 1137-1148, ISSN: 1061-4036Genetic studies promise to provide insight into the molecular mechanisms underlying type 2 diabetes (T2D). Variants associated with T2D are often located in tissue-specific enhancer clustersor super-enhancers. So far, such domains have been defined through clustering of enhancers in linear genome maps rather than in 3D space. Furthermore, their target genes are often unknown. We have now created promoter capture Hi-C maps in human pancreatic islets. This linked diabetes-associated enhancers with their target genes, often located hundreds of kilobases away. It also revealed >1300 groups of islet enhancers, super-enhancers and active promoters that form 3D hubs, some of which show coordinated glucose-dependent activity. We demonstrate that genetic variation in hubs impacts insulin secret ion heritability, and show that hub annotations can be used for polygenic scores that predict T2D risk driven by islet regulatory variants. Human islet 3D chromatin architecture, therefore, provides a framework for interpretation of T2D GWAS signals.
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Journal articleKalna V, Yang Y, Peghaire C, et al., 2019,
The transcription factor ERG regulates super-enhancers associated with an endothelial-specific gene expression program
, Circulation Research, Vol: 124, Pages: 1337-1349, ISSN: 0009-7330Rationale:The ETS (E-26 transformation-specific) transcription factor ERG (ETS-related gene) is essential for endothelial homeostasis, driving expression of lineage genes and repressing proinflammatory genes. Loss of ERG expression is associated with diseases including atherosclerosis. ERG’s homeostatic function is lineage-specific, because aberrant ERG expression in cancer is oncogenic. The molecular basis for ERG lineage-specific activity is unknown. Transcriptional regulation of lineage specificity is linked to enhancer clusters (super-enhancers).Objective:To investigate whether ERG regulates endothelial-specific gene expression via super-enhancers.Methods and Results:Chromatin immunoprecipitation with high-throughput sequencing in human umbilical vein endothelial cells showed that ERG binds 93% of super-enhancers ranked according to H3K27ac, a mark of active chromatin. These were associated with endothelial genes such as DLL4 (Delta-like protein 4), CLDN5 (claudin-5), VWF (von Willebrand factor), and CDH5 (VE-cadherin). Comparison between human umbilical vein endothelial cell and prostate cancer TMPRSS2 (transmembrane protease, serine-2):ERG fusion-positive human prostate epithelial cancer cell line (VCaP) cells revealed distinctive lineage-specific transcriptome and super-enhancer profiles. At a subset of endothelial super-enhancers (including DLL4 and CLDN5), loss of ERG results in significant reduction in gene expression which correlates with decreased enrichment of H3K27ac and MED (Mediator complex subunit)-1, and reduced recruitment of acetyltransferase p300. At these super-enhancers, co-occupancy of GATA2 (GATA-binding protein 2) and AP-1 (activator protein 1) is significantly lower compared with super-enhancers that remained constant following ERG inhibition. These data suggest distinct mechanisms of super-enhancer regulation in endothelial cells and highlight the unique role of ERG in controlling a core subset of super-enhancers. Most disease-assoc
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Journal articleRhodes CJ, Batai K, Bleda M, et al., 2019,
Genetic determinants of risk in pulmonary arterial hypertension: international case-control studies and meta-analysis
, Lancet Respiratory Medicine, Vol: 7, Pages: 227-238, ISSN: 2213-2600BackgroundRare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes.MethodsWe did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses.FindingsA locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55–2·08], p=5·13 × 10–15) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42–1·71], p=7·65 × 10–20) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25–1·48], p=1·69 × 10–12; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-media
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Journal articleFont-Cunill B, Arnes L, Ferrer J, et al., 2018,
Long non-coding RNAs as local regulators of pancreatic islet transcription factor genes
, Frontiers in Genetics, Vol: 9, Pages: 1-9, ISSN: 1664-8021The transcriptional programs of differentiated cells are tightly regulated by interactions between cell type-specific transcription factors and cis-regulatory elements. Long non-coding RNAs (lncRNAs) have emerged as additional regulators of gene transcription. Current evidence indicates that lncRNAs are a very heterogeneous group of molecules. For example, selected lncRNAs have been shown to regulate gene expression in cis or trans, although in most cases the precise underlying molecular mechanisms is unknown. Recent studies have uncovered a large number of lncRNAs that are selectively expressed in pancreatic islet cells, some of which were shown to regulate β cell transcriptional programs. A subset of such islet lncRNAs appears to control the expression of β cell-specific transcription factor (TF) genes by local cis-regulation. In this review, we discuss current knowledge of molecular mechanisms underlying cis-regulatory lncRNAs and discuss challenges involved in using genetic perturbations to define their function. We then discuss known examples of pancreatic islet lncRNAs that appear to exert cis-regulation of TF genes. We propose that cis-regulatory lncRNAs could represent a molecular target for modulation of diabetes-relevant genes.
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Journal articleMillership S, Da Silva Xavier G, Choudhury A, et al., 2018,
Neuronatin regulates pancreatic beta cell insulin content and secretion
, Journal of Clinical Investigation, Vol: 128, Pages: 3369-3381, ISSN: 0021-9738Neuronatin (Nnat) is an imprinted gene implicated in human obesity and widely expressed in neuroendocrine and metabolic tissues in a hormone and nutrient-sensitive manner. However, its molecular and cellular functions and precise role in organismal physiology remain only partly defined. Here we demonstrate that mice lacking Nnat globally or specifically in β cells display impaired glucose-stimulated insulin secretion leading to defective glucose handling under conditions of nutrient-excess. In contrast, we report no evidence for any feeding or body weight phenotypes in global Nnat null mice. At the molecular level neuronatin augments insulin signal peptide cleavage by binding to the signal peptidase complex and facilitates translocation of the nascent preprohormone. Loss of neuronatin expression in β cells therefore reduces insulin content and blunts glucose-stimulated insulin secretion. Nnat expression, in turn, is glucose-regulated. This mechanism therefore represents a novel site of nutrient-sensitive control of β cell function and whole animal glucose homeostasis. These data also suggest a potential wider role for Nnat in the regulation of metabolism through the modulation of peptide processing events.
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Journal articleBonas-Guarch S, Guindo-Martinez M, Miguel-Escalada I, et al., 2018,
Publisher correction: Re-analysis of public genetic data reveals a rare X-chromosomal variant associated with type 2 diabetes (vol 9, 321, 2018)
, Nature Communications, Vol: 9, ISSN: 2041-1723Correction to:Nature Communicationshttps://doi.org/10.1038/s41467-017-02380-9, published online 22 January 2018In the originally published version of this Article, the affiliation details for Santi González, Jian’an Luan and Claudia Langenberg wereinadvertently omitted. Santi González should have been affiliated with 'Barcelona Supercomputing Center (BSC), Joint BSC-CRG-IRBResearch Program in Computational Biology, 08034 Barcelona, Spain’, and Jian’an Luan and Claudia Langenberg should have beenaffiliated with‘MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus,Cambridge CB2 0QQ, UK’. Furthermore, the abstract contained an error in the SNP ID for the rare variant in chromosome Xq23,which was incorrectly given as rs146662057 and should have been rs146662075. These errors have now been corrected in both the PDFand HTML versions of the Article.
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Journal articleMartinez-Sanchez A, Nguyen-Tu M-S, Cebola I, et al., 2018,
MiR-184 expression is regulated by AMPK in pancreatic islets.
, FASEB Journal, Vol: 32, Pages: 2587-2600, ISSN: 0892-6638AMPK is a critical energy sensor and target for widely used antidiabetic drugs. In β-cells, elevated glucose concentrations lower AMPK activity, and the ablation of both catalytic subunits (βAMPKdKO mice) impairs insulin secretion in vivo and β-cell identity. MicroRNAs (miRNAs) are small RNAs that silence gene expression that are essential for pancreatic β-cell function and identity and altered in diabetes. Here, we have explored the miRNAs acting downstream of AMPK in mouse and human β-cells. We identified 14 down-regulated and 9 up-regulated miRNAs in βAMPKdKO vs. control islets. Gene ontology analysis of targeted transcripts revealed enrichment in pathways important for β-cell function and identity. The most down-regulated miRNA was miR-184 (miR-184-3p), an important regulator of β-cell function and compensatory expansion that is controlled by glucose and reduced in diabetes. We demonstrate that AMPK is a potent regulator and an important mediator of the negative effects of glucose on miR-184 expression. Additionally, we reveal sexual dimorphism in miR-184 expression in mouse and human islets. Collectively, these data demonstrate that glucose-mediated changes in AMPK activity are central for the regulation of miR-184 and other miRNAs in islets and provide a link between energy status and gene expression in β-cells.-Martinez-Sanchez, A., Nguyen-Tu, M.-S., Cebola, I., Yavari, A., Marchetti, P., Piemonti, L., de Koning, E., Shapiro, A. M. J., Johnson, P., Sakamoto, K., Smith, D. M., Leclerc, I., Ashrafian, H., Ferrer, J., Rutter, G. A. MiR-184 expression is regulated by AMPK in pancreatic islets.
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Journal articleBonas-Guarch S, Guindo-Martinez M, Miguel-Escalada I, et al., 2018,
Re-analysis of public genetic data reveals a rare X-chromosomal variant associated with type 2 diabetes
, Nature Communications, Vol: 9, ISSN: 2041-1723The reanalysis of existing GWAS data represents a powerful and cost-effective opportunity to gain insights into the genetics of complex diseases. By reanalyzing publicly available type 2 diabetes (T2D) genome-wide association studies (GWAS) data for 70,127 subjects, we identify seven novel associated regions, five driven by common variants (LYPLAL1, NEUROG3, CAMKK2, ABO, and GIP genes), one by a low-frequency (EHMT2), and one driven by a rare variant in chromosome Xq23, rs146662075, associated with a twofold increased risk for T2D in males. rs146662075 is located within an active enhancer associated with the expression of Angiotensin II Receptor type 2 gene (AGTR2), a modulator of insulin sensitivity, and exhibits allelic specific activity in muscle cells. Beyond providing insights into the genetics and pathophysiology of T2D, these results also underscore the value of reanalyzing publicly available data using novel genetic resources and analytical approaches.
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Journal articleGudmundsdottir V, Pedersen HK, Allebrandt KV, et al., 2018,
Integrative network analysis highlights biological processes underlying GLP-1 stimulated insulin secretion: A DIRECT study.
, PLoS ONE, Vol: 13, ISSN: 1932-6203Glucagon-like peptide 1 (GLP-1) stimulated insulin secretion has a considerable heritable component as estimated from twin studies, yet few genetic variants influencing this phenotype have been identified. We performed the first genome-wide association study (GWAS) of GLP-1 stimulated insulin secretion in non-diabetic individuals from the Netherlands Twin register (n = 126). This GWAS was enhanced using a tissue-specific protein-protein interaction network approach. We identified a beta-cell protein-protein interaction module that was significantly enriched for low gene scores based on the GWAS P-values and found support at the network level in an independent cohort from Tübingen, Germany (n = 100). Additionally, a polygenic risk score based on SNPs prioritized from the network was associated (P < 0.05) with glucose-stimulated insulin secretion phenotypes in up to 5,318 individuals in MAGIC cohorts. The network contains both known and novel genes in the context of insulin secretion and is enriched for members of the focal adhesion, extracellular-matrix receptor interaction, actin cytoskeleton regulation, Rap1 and PI3K-Akt signaling pathways. Adipose tissue is, like the beta-cell, one of the target tissues of GLP-1 and we thus hypothesized that similar networks might be functional in both tissues. In order to verify peripheral effects of GLP-1 stimulation, we compared the transcriptome profiling of ob/ob mice treated with liraglutide, a clinically used GLP-1 receptor agonist, versus baseline controls. Some of the upstream regulators of differentially expressed genes in the white adipose tissue of ob/ob mice were also detected in the human beta-cell network of genes associated with GLP-1 stimulated insulin secretion. The findings provide biological insight into the mechanisms through which the effects of GLP-1 may be modulated and highlight a potential role of the beta-cell expressed genes RYR2, GDI2, KIAA0232, COL4A1 and COL4A2 in GLP-1 stimulated insulin sec
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Journal articleMercader JM, Liao RG, Bell AD, et al., 2017,
A loss-of-function splice acceptor variant in IGF2 is protective for type 2 diabetes
, Diabetes, Vol: 66, Pages: 2903-2914, ISSN: 0012-1797Type 2 diabetes (T2D) affects more than 415 million people worldwide, and its costs to the health care system continue to rise. To identify common or rare genetic variation with potential therapeutic implications for T2D, we analyzed and replicated genome-wide protein coding variation in a total of 8,227 individuals with T2D and 12,966 individuals without T2D of Latino descent. We identified a novel genetic variant in the IGF2 gene associated with ∼20% reduced risk for T2D. This variant, which has an allele frequency of 17% in the Mexican population but is rare in Europe, prevents splicing between IGF2 exons 1 and 2. We show in vitro and in human liver and adipose tissue that the variant is associated with a specific, allele-dosage–dependent reduction in the expression of IGF2 isoform 2. In individuals who do not carry the protective allele, expression of IGF2 isoform 2 in adipose is positively correlated with both incidence of T2D and increased plasma glycated hemoglobin in individuals without T2D, providing support that the protective effects are mediated by reductions in IGF2 isoform 2. Broad phenotypic examination of carriers of the protective variant revealed no association with other disease states or impaired reproductive health. These findings suggest that reducing IGF2 isoform 2 expression in relevant tissues has potential as a new therapeutic strategy for T2D, even beyond the Latin American population, with no major adverse effects on health or reproduction.
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