Publications
134 results found
Ferrer J, Kalisz M, Beucher A, et al., 2019, HNF1A recruits UTX to activate a differentiation program that suppresses pancreatic cancer, Publisher: bioRxiv
Miguel-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: 1061-4036
Genetic 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.
Ferrer J, 2019, HNF1A recruits KDM6A to activate diffentiated acinar cell programs that suppress pancreatic cancer, The EMBO Journal, ISSN: 0261-4189
Dawed AY, Zhou K, van Leeuwen N, et al., 2019, Variation in the Plasma Membrane Monoamine Transporter (PMAT) (Encoded by <i>SLC29A4</i>) and Organic Cation Transporter 1 (OCT1) (Encoded by <i>SLC22A1</i>) and Gastrointestinal Intolerance to Metformin in Type 2 Diabetes: An IMI DIRECT Study, DIABETES CARE, Vol: 42, Pages: 1027-1033, ISSN: 0149-5992
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- Citations: 32
Kalna 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: 0009-7330
Rationale: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
Rhodes 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: 2213-2600
BackgroundRare 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
Font-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: 1664-8021
The 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.
Miguel-Escalada I, Bonàs-Guarch S, Cebola I, et al., 2018, Human pancreatic islet 3D chromatin architecture provides insights into the genetics of type 2 diabetes
Genetic 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 regions (enhancer clusters, stretch enhancers or 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 generally 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 further revealed sets of islet enhancers, super-enhancers and active promoters that form 3D higher-order hubs, some of which show coordinated glucose-dependent activity. Hub genetic variants impact the heritability of insulin secretion, and help identify individuals in whom genetic variation of islet function is important for T2D. Human islet 3D chromatin architecture thus provides a framework for interpretation of T2D GWAS signals.
Millership 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: 0021-9738
Neuronatin (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.
de Lichtenberg KH, Seymour PA, Jørgensen MC, et al., 2018, Notch Controls Multiple Pancreatic Cell Fate Regulators Through Direct Hes1-mediated Repression
<jats:title>Abstract</jats:title><jats:p>Notch signaling and its effector Hes1 regulate multiple cell fate choices in the developing pancreas, but few direct target genes are known. Here we use transcriptome analyses combined with chromatin immunoprecipitation with next-generation sequencing (ChIP-seq) to identify direct target genes of Hes1. ChIP-seq analysis of endogenous Hes1 in 266-6 cells, a model of multipotent pancreatic progenitor cells, revealed high-confidence peaks associated with 354 genes. Among these were genes important for tip/trunk segregation such as<jats:italic>Ptf1a</jats:italic>and<jats:italic>Nkx6-1</jats:italic>, genes involved in endocrine differentiation such as<jats:italic>Insm1</jats:italic>and<jats:italic>Dll4</jats:italic>, and genes encoding non-pancreatic basic-Helic-Loop-Helix (bHLH) factors such as<jats:italic>Neurog2</jats:italic>and<jats:italic>Ascl1</jats:italic>. Surprisingly, we find that Hes1 binds a large number of loci previously reported to bind Ptf1a, including a site downstream of the<jats:italic>Nkx6-1</jats:italic>gene. Notably, we find a number of Hes1 bound genes that are upregulated by γ-secretase inhibition in pancreas explants independently of<jats:italic>Neurog3</jats:italic>function, including the tip progenitor/acinar genes;<jats:italic>Ptf1a, Gata4, Bhlha15</jats:italic>, and<jats:italic>Gfi1</jats:italic>. Together, our data suggest that Notch signaling suppress the tip cell fate by Hes1-mediated repression of the tip-specific gene regulatory network module that includes transcriptional regulators such as Ptf1a, Gata4, Mist1, and Gfi1. Our data also uncover new molecular targets of Notch signaling that may be important for controlling cell fate choices in pancreas development.</jats:p>
de Lichtenberg KH, Funa N, Nakic N, et al., 2018, Genome-Wide Identification of HES1 Target Genes Uncover Novel Roles for HES1 in Pancreatic Development
<jats:title>Abstract</jats:title><jats:p>Notch signalling and the downstream effector HES1 is required for multiple pancreatic cell fate choices during development, but the direct target genes remain poorly characterised. Here we identify direct HES1 target genes on a genome-wide scale using ChIP-seq and RNA-seq analyses combined with human embryonic stem cell (hESC) directed differentiation of CRISPR/Cas9-generated<jats:italic>HES1</jats:italic><jats:sup><jats:italic>-/-</jats:italic></jats:sup>mutant hESC lines. We found that HES1 binds to a distinct set of endocrine-specific genes, a set of genes encoding basic Helix-Loop-Helix (bHLH) proteins not normally expressed in the pancreas, genes in the Notch pathway, and the known HES1 target NEUROG3. RNA-seq analysis of wild type,<jats:italic>HES1</jats:italic><jats:sup>-/-</jats:sup>,<jats:italic>NEUROG3</jats:italic><jats:sup>-/-</jats:sup>, and<jats:italic>HES1</jats:italic><jats:sup>-/-</jats:sup><jats:italic>NEUROG</jats:italic>3<jats:sup>-/-</jats:sup>mutant hESC lines allowed us to uncover NEUROG3-independent, direct HES1 target genes. Among the HES1 bound genes that were derepressed in<jats:italic>HES1</jats:italic><jats:sup>-/-</jats:sup><jats:italic>NEUROG3</jats:italic><jats:sup>-/-</jats:sup>cells compared to<jats:italic>NEUROG3</jats:italic><jats:sup>-/-</jats:sup>cells, we found members of the endocrine-specific gene set, the Notch pathway genes<jats:italic>DLL1</jats:italic>,<jats:italic>DLL4</jats:italic>, and<jats:italic>HEY1</jats:italic>, as well as the non-pancreatic bHLH genes<jats:italic>ASCL1</jats:italic>and<jats:italic>ATOH1</jats:italic>. We also found a large number of transcripts specific to the intestinal secretor
Bonas-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: 2041-1723
Correction 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.
Mereu E, Iacono G, Guillaumet-Adkins A, et al., 2018, matchSCore: Matching Single-Cell Phenotypes Across Tools and Experiments
<jats:title>Abstract</jats:title><jats:p>Single-cell transcriptomics allows the identification of cellular types, subtypes and states through cell clustering. In this process, similar cells are grouped before determining co-expressed marker genes for phenotype inference. The performance of computational tools is directly associated to their marker identification accuracy, but the lack of an optimal solution challenges a systematic method comparison. Moreover, phenotypes from different studies are challenging to integrate, due to varying resolution, methodology and experimental design. In this work we introduce <jats:italic>matchSCore (<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://github.com/elimereu/matchSCore">https://github.com/elimereu/matchSCore</jats:ext-link>)</jats:italic>, an approach to match cell populations fast across tools, experiments and technologies. We compared 14 computational methods and evaluated their accuracy in clustering and gene marker identification in simulated data sets. We further used <jats:italic>matchSCore</jats:italic> to project cell type identities across mouse and human cell atlas projects. Despite originating from different technologies, cell populations could be matched across data sets, allowing the assignment of clusters to reference maps and their annotation.</jats:p>
Martinez-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: 0892-6638
AMPK 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.
Bonas-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: 2041-1723
The 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.
Gudmundsdottir 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: 1932-6203
Glucagon-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
Mercader 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: 0012-1797
Type 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.
Wang H, Bender A, Wang P, et al., 2017, Insights into beta cell regeneration for diabetes via integration of molecular landscapes in human insulinomas, Nature Communications, Vol: 8, Pages: 1-15, ISSN: 2041-1723
Although diabetes results in part from a deficiency of normal pancreatic beta cells, inducing human beta cells to regenerate is difficult. Reasoning that insulinomas hold the “genomic recipe” for beta cell expansion, we surveyed 38 human insulinomas to obtain insights into therapeutic pathways for beta cell regeneration. An integrative analysis of whole-exome and RNA-sequencing data was employed to extensively characterize the genomic and molecular landscape of insulinomas relative to normal beta cells. Here, we show at the pathway level that the majority of the insulinomas display mutations, copy number variants and/or dysregulation of epigenetic modifying genes, most prominently in the polycomb and trithorax families. Importantly, these processes are coupled to co-expression network modules associated with cell proliferation, revealing candidates for inducing beta cell regeneration. Validation of key computational predictions supports the concept that understanding the molecular complexity of insulinoma may be a valuable approach to diabetes drug discovery.
van Arensbergen J, Dussaud S, Pardanaud-Glavieux C, et al., 2017, A distal intergenic region controls pancreatic endocrine differentiation by acting as a transcriptional enhancer and as a polycomb response element, PLOS ONE, Vol: 12, ISSN: 1932-6203
Lineage-selective expression of developmental genes is dependent on the interplay between activating and repressive mechanisms. Gene activation is dependent on cell-specific transcription factors that recognize transcriptional enhancer sequences. Gene repression often depends on the recruitment of Polycomb group (PcG) proteins, although the sequences that underlie the recruitment of PcG proteins, also known as Polycomb response elements (PREs), remain poorly understood in vertebrates. While distal PREs have been identified in mammals, a role for positive-acting enhancers in PcG-mediated repression has not been described. Here we have used a highly efficient procedure based on lentiviral-mediated transgenesis to carry out in vivo fine-mapping of, cis-regulatory sequences that control lineage-specific activation of Neurog3, a master regulator of pancreatic endocrine differentiation. Our findings reveal an enhancer region that is sufficient to drive correct spacio-temporal expression of Neurog3 and demonstrate that this same region serves as a PRE in alternative lineages where Neurog3 is inactive.
Akerman I, Tu Z, Beucher A, et al., 2017, Human pancreatic β cell incRNAs control cell-specific regulatory networks, Cell Metabolism, Vol: 25, Pages: 400-411, ISSN: 1932-7420
Recent studies have uncovered thousands of long non-coding RNAs (lncRNAs) in human pancreatic β cells. β cell lncRNAs are often cell type specific and exhibit dynamic regulation during differentiation or upon changing glucose concentrations. Although these features hint at a role of lncRNAs in β cell gene regulation and diabetes, the function of β cell lncRNAs remains largely unknown. In this study, we investigated the function of β cell-specific lncRNAs and transcription factors using transcript knockdowns and co-expression network analysis. This revealed lncRNAs that function in concert with transcription factors to regulate β cell-specific transcriptional networks. We further demonstrate that the lncRNA PLUTO affects local 3D chromatin structure and transcription of PDX1, encoding a key β cell transcription factor, and that both PLUTO and PDX1 are downregulated in islets from donors with type 2 diabetes or impaired glucose tolerance. These results implicate lncRNAs in the regulation of β cell-specific transcription factor networks.
Johnston NR, Mitchell RK, Haythorne E, et al., 2016, Beta cell hubs dictate pancreatic islet responses to glucose, Cell Metabolism, Vol: 24, Pages: 389-401, ISSN: 1932-7420
The arrangement of beta cells within islets of Langerhans is critical for insulin release through thegeneration of rhythmic activity. A privileged role for individual beta cells in orchestrating theseresponses has long-been suspected, but not directly demonstrated. We show here that the beta cellpopulation in situ is operationally heterogeneous. Mapping of islet functional architecturerevealed the presence of hub cells with pacemaker properties, which remain stable over recordingperiods of 2-3 hours. Using a dual optogenetic/photopharmacological strategy, silencing of hubsabolished coordinated islet responses to glucose, whereas specific stimulation restoredcommunication patterns. Hubs were metabolically-adapted and targeted by both proinflammatoryand glucolipotoxic insults to induce widespread beta cell dysfunction. Thus, theislet is wired by hubs, whose failure may contribute to type 2 diabetes mellitus.
Ferrer J, Real FX, 2016, The <i>cis</i>-regulatory switchboard of pancreatic ductal cancer, EMBO JOURNAL, Vol: 35, Pages: 558-560, ISSN: 0261-4189
Arnes L, Akerman I, Balderes DA, et al., 2016, βlinc1 encodes a long noncoding RNA that regulates islet β-cell formation and function, Genes & Development, Vol: 30, Pages: 502-507, ISSN: 1549-5477
Pancreatic β cells are responsible for maintaining glucose homeostasis; their absence or malfunction results in diabetes mellitus. Although there is evidence that long noncoding RNAs (lncRNAs) play important roles in development and disease, none have been investigated in vivo in the context of pancreas development. In this study, we demonstrate that βlinc1 (β-cell long intergenic noncoding RNA 1), a conserved lncRNA, is necessary for the specification and function of insulin-producing β cells through the coordinated regulation of a number of islet-specific transcription factors located in the genomic vicinity of βlinc1. Furthermore, deletion of βlinc1 results in defective islet development and disruption of glucose homeostasis in adult mice.
Horikoshi M, Pasquali L, Wiltshire S, et al., 2016, Transancestral fine-mapping of four type 2 diabetes susceptibility loci highlights potential causal regulatory mechanisms, Human Molecular Genetics, Vol: 25, Pages: 2070-2081, ISSN: 1460-2083
To gain insight into potential regulatory mechanisms through which the effects of variants at four established type 2 diabetes (T2D) susceptibility loci (CDKAL1, CDKN2A-B, IGF2BP2 and KCNQ1) are mediated, we undertook transancestral fine-mapping in 22 086 cases and 42 539 controls of East Asian, European, South Asian, African American and Mexican American descent. Through high-density imputation and conditional analyses, we identified seven distinct association signals at these four loci, each with allelic effects on T2D susceptibility that were homogenous across ancestry groups. By leveraging differences in the structure of linkage disequilibrium between diverse populations, and increased sample size, we localised the variants most likely to drive each distinct association signal. We demonstrated that integration of these genetic fine-mapping data with genomic annotation can highlight potential causal regulatory elements in T2D-relevant tissues. These analyses provide insight into the mechanisms through which T2D association signals are mediated, and suggest future routes to understanding the biology of specific disease susceptibility loci.
De Vas M, Ferrer J, 2016, Can Insulin Production Suppress β Cell Growth?, CELL METABOLISM, Vol: 23, Pages: 4-5, ISSN: 1550-4131
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Gaulton KJ, Ferreira T, Lee Y, et al., 2015, Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci., Nature Genetics, Vol: 47, Pages: 1415-1425, ISSN: 1546-1718
We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
Miguel Escalada I, Pasquali L, Ferrer J, 2015, Transcriptional enhancers: functional insights and role in human disease, Current Opinion in Genetics & Development, Vol: 33, Pages: 71-76, ISSN: 0959-437X
In recent years, studies of cis-regulatory mechanisms have evolved from a predominant focus on promoter regions to the realization that spatial and temporal gene regulation is frequently driven by long-range enhancer clusters that operate within chromosomal compartments. This increased understanding of genome function, together with the emergence of technologies that enable whole-genome sequencing of patients’ DNAs, open the prospect of dissecting the role of cis-regulatory defects in human disease. In this review we discuss how recent epigenomic studies have provided insights into the function of transcriptional enhancers. We then present examples that illustrate how integrative genomics can help uncover enhancer sequence variants underlying Mendelian and common polygenic human disease.
Zhao L, Oliver E, Maratou K, et al., 2015, The zinc transporter, ZIP12, regulates the pulmonary vascular response to chronic hypoxia, Nature, Vol: 524, Pages: 356-360, ISSN: 0028-0836
The typical response of the adult mammalian pulmonary circulation to a low oxygen environment is vasoconstriction and structural remodelling of pulmonary arterioles, leading to chronic elevation of pulmonary artery pressure (pulmonary hypertension) and right ventricular hypertrophy. Some mammals, however, exhibit genetic resistance to hypoxia-induced pulmonary hypertension1, 2, 3. We used a congenic breeding program and comparative genomics to exploit this variation in the rat and identified the gene Slc39a12 as a major regulator of hypoxia-induced pulmonary vascular remodelling. Slc39a12 encodes the zinc transporter ZIP12. Here we report that ZIP12 expression is increased in many cell types, including endothelial, smooth muscle and interstitial cells, in the remodelled pulmonary arterioles of rats, cows and humans susceptible to hypoxia-induced pulmonary hypertension. We show that ZIP12 expression in pulmonary vascular smooth muscle cells is hypoxia dependent and that targeted inhibition of ZIP12 inhibits the rise in intracellular labile zinc in hypoxia-exposed pulmonary vascular smooth muscle cells and their proliferation in culture. We demonstrate that genetic disruption of ZIP12 expression attenuates the development of pulmonary hypertension in rats housed in a hypoxic atmosphere. This new and unexpected insight into the fundamental role of a zinc transporter in mammalian pulmonary vascular homeostasis suggests a new drug target for the pharmacological management of pulmonary hypertension.
Spaeth JM, Hunter CS, Bonatakis L, et al., 2015, The FOXP1, FOXP2 and FOXP4 transcription factors are required for islet alpha cell proliferation and function in mice, Diabetologia, Vol: 58, Pages: 1836-1844, ISSN: 1432-0428
Aims/hypothesis Several forkhead box (FOX) transcriptionfactor family members have important roles in controllingpancreatic cell fates and maintaining beta cell mass and function,including FOXA1, FOXA2 and FOXM1. In this studywe have examined the importance of FOXP1, FOXP2 andFOXP4 of the FOXP subfamily in islet cell developmentand function.Methods Mice harbouring floxed alleles for Foxp1, Foxp2and Foxp4 were crossed with pan-endocrine Pax6-Cre transgenicmice to generate single and compound Foxp mutantmice. Mice were monitored for changes in glucose toleranceby IPGTT, serum insulin and glucagon levels by radioimmunoassay,and endocrine cell development and proliferation byimmunohistochemistry. Gene expression and glucosestimulatedhormone secretion experiments were performedwith isolated islets.Results Only the triple-compound Foxp1/2/4 conditionalknockout (cKO) mutant had an overt islet phenotype, manifestedphysiologically by hypoglycaemia andhypoglucagonaemia. This resulted from the reduction inglucagon-secreting alpha cell mass and function. The proliferationof alpha cells was profoundly reduced in Foxp1/2/4cKO islets through the effects on mediators of replication (i.e.decreased Ccna2, Ccnb1 and Ccnd2 activators, and increasedCdkn1a inhibitor). Adult islet Foxp1/2/4 cKO beta cells secreteinsulin normally while the remaining alpha cells haveimpaired glucagon secretion.Conclusions/interpretation Collectively, these findings revealan important role for the FOXP1, 2, and 4 proteins ingoverning postnatal alpha cell expansion and function.
Ferrer J, Cebola I, Rodríguez-Seguí SA, et al., 2015, TEAD and YAP regulate the enhancer network of human embryonic pancreatic progenitors, Nature Cell Biology, Vol: 17, Pages: 615-626, ISSN: 1476-4679
The genomic regulatory programmes that underlie human organogenesis are poorly understood. Pancreas development, in particular, has pivotal implications for pancreatic regeneration, cancer and diabetes. We have now characterized the regulatory landscape of embryonic multipotent progenitor cells that give rise to all pancreatic epithelial lineages. Using human embryonic pancreas and embryonic-stem-cell-derived progenitors we identify stage-specific transcripts and associated enhancers, many of which are co-occupied by transcription factors that are essential for pancreas development. We further show that TEAD1, a Hippo signalling effector, is an integral component of the transcription factor combinatorial code of pancreatic progenitor enhancers. TEAD and its coactivator YAP activate key pancreatic signalling mediators and transcription factors, and regulate the expansion of pancreatic progenitors. This work therefore uncovers a central role for TEAD and YAP as signal-responsive regulators of multipotent pancreatic progenitors, and provides a resource for the study of embryonic development of the human pancreas.
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