124 results found
Atla G, Bonas-Guarch S, Cuenca-Ardura M, et al., 2022, Genetic regulation of RNA splicing in human pancreatic islets, Genome Biology, ISSN: 1474-7596
Background: Non‑coding genetic variants that influence gene transcription in pancreatic islets play a major role in the susceptibility to type 2 diabetes (T2D), and likely also contribute to type 1 diabetes (T1D) risk. For many loci, however, the mechanisms through which non‑coding variants influence diabetes susceptibility are unknown. Results: We examine splicing QTLs (sQTLs) in pancreatic islets from 399 human donors and observe that genetic variation has a widespread influence on splicing of genes with established roles in islet biology and diabetes. In parallel, we profile expression QTLs (eQTLs) and use transcriptome‑wide association as well as genetic co‑localization studies to assign islet sQTLs or eQTLs to T2D and T1D susceptibility signals, many of which lack candidate effector genes. This analysis reveals biologically plausible mechanisms, including the association of T2D with an sQTL that creates a nonsense isoform in ERO1B, a regulator of ER‑stress and proinsulin biosynthesis. The expanded list of T2D risk effector genes reveals overrepresented pathways, including regulators of G‑protein‑mediated cAMP production. The analysis of sQTLs also reveals candidate effector genesfor T1D susceptibility such as DCLRE1B, a senescence regulator, and lncRNA MEG3.Conclusions: These data expose widespread effects of common genetic variants on RNA splicing in pancreatic islets. The results support a role for splicing variation in diabetes susceptibility, and offer a new set of genetic targets with potential therapeutic benefit.
Cuenca-Ardura M, De Vas M, Balboa D, et al., 2022, Genome-wide CRISPR screens identify therapeutic targets for HNF1A-deficient diabetes, Publisher: SPRINGER, Pages: S162-S162, ISSN: 0012-186X
Miguel-Escalada I, Maestro MÁ, Balboa D, et al., 2022, Pancreas agenesis mutations disrupt a lead enhancer controlling a developmental enhancer cluster., Developmental Cell, Vol: 57, Pages: 1922-1936.e9, ISSN: 1534-5807
Sequence variants in cis-acting enhancers are important for polygenic disease, but their role in Mendelian disease is poorly understood. Redundancy between enhancers that regulate the same gene is thought to mitigate the pathogenic impact of enhancer mutations. Recent findings, however, have shown that loss-of-function mutations in a single enhancer near PTF1A cause pancreas agenesis and neonatal diabetes. Using mouse and human genetic models, we show that this enhancer activates an entire PTF1A enhancer cluster in early pancreatic multipotent progenitors. This leading role, therefore, precludes functional redundancy. We further demonstrate that transient expression of PTF1A in multipotent progenitors sets in motion an epigenetic cascade that is required for duct and endocrine differentiation. These findings shed insights into the genome regulatory mechanisms that drive pancreas differentiation. Furthermore, they reveal an enhancer that acts as a regulatory master key and is thus vulnerable to pathogenic loss-of-function mutations.
Beucher A, Miguel Escalada I, Balboa D, et al., 2022, HASTER lncRNA promoter is a cis-acting transcriptional stabilizer of HNF1A, Nature Cell Biology, ISSN: 1465-7392
The biological purpose of long noncoding RNAs (lncRNAs) is poorly understood. Haploinsufficient mutations in HNF1A, encoding a homeodomain transcription factor, cause diabetes mellitus. Here we examined HASTER, the promoter of a lncRNA antisense to HNF1A. Using mouse and human models, we show that HASTER maintains cell-specific physiological HNF1A concentrations through positive and negative feedback loops. Pancreatic β cells from Haster mutant mice consequently showed variegated HNF1A silencing or overexpression, resulting in hyperglycemia.HASTER-dependent negative feedback was essential to prevent HNF1A binding to inappropriate genomic regions. We demonstrate that the HASTER promoter DNA, rather than the lncRNA, modulates HNF1A promoter-enhancer interactions in cis, and thereby regulates HNF1A transcription. Our studies expose a cis-regulatory element that is unlike classic enhancers or silencers, but instead stabilizes the transcription of its target gene, and ensures the fidelity of a cell-specific transcription factor program. They also show that disruption of a mammalian lncRNA promoter can cause diabetes mellitus.
Mahajan A, Spracklen CN, Zhang W, et al., 2022, Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation, NATURE GENETICS, Vol: 54, Pages: 560-+, ISSN: 1061-4036
Nagao M, Fukuda A, Omatsu M, et al., 2022, Concurrent Activation of Kras and Canonical Wnt Signaling Induces Premalignant Lesions That Progress to Extrahepatic Biliary Cancer in Mice., Cancer Res, Vol: 82, Pages: 1803-1817
Biliary cancer has long been known to carry a poor prognosis, yet the molecular pathogenesis of carcinoma of the extrahepatic biliary system and its precursor lesions remains elusive. Here we investigated the role of Kras and canonical Wnt pathways in the tumorigenesis of the extrahepatic bile duct (EHBD) and gall bladder (GB). In mice, concurrent activation of Kras and Wnt pathways induced biliary neoplasms that resembled human intracholecystic papillary-tubular neoplasm (ICPN) and biliary intraepithelial neoplasia (BilIN), putative precursors to invasive biliary cancer. At a low frequency, these lesions progressed to adenocarcinoma in a xenograft model, establishing them as precancerous lesions. Global gene expression analysis revealed increased expression of genes associated with c-Myc and TGFβ pathways in mutant biliary spheroids. Silencing or pharmacologic inhibition of c-Myc suppressed proliferation of mutant biliary spheroids, whereas silencing of Smad4/Tgfbr2 or pharmacologic inhibition of TGFβ signaling increased proliferation of mutant biliary spheroids and cancer formation in vivo. Human ICPNs displayed activated Kras and Wnt signals and c-Myc and TGFβ pathways. Thus, these data provide direct evidence that concurrent activation of the Kras and canonical Wnt pathways results in formation of ICPN and BilIN, which could develop into biliary cancer. SIGNIFICANCE: This work shows how dysregulation of canonical cell growth pathways drives precursors to biliary cancers and identifies several molecular vulnerabilities as potential therapeutic targets in these precursors to prevent oncogenic progression.
Alonso L, Piron A, Moran I, et al., 2021, TIGER: The gene expression regulatory variation landscape of human pancreatic islets, CELL REPORTS, Vol: 37, ISSN: 2211-1247
Rovira M, Atla G, Maestro MA, et al., 2021, REST is a major negative regulator of endocrine differentiation during pancreas organogenesis, Genes & Development, Vol: 35, Pages: 1229-1242, ISSN: 0890-9369
Multiple transcription factors have been shown to promote pancreatic β-cell differentiation, yet much less is known about negative regulators. Earlier epigenomic studies suggested that the transcriptional repressor REST could be a suppressor of endocrinogenesis in the embryonic pancreas. However, pancreatic Rest knockout mice failed to show abnormal numbers of endocrine cells, suggesting that REST is not a major regulator of endocrine differentiation. Using a different conditional allele that enables profound REST inactivation, we observed a marked increase in pancreatic endocrine cell formation. REST inhibition also promoted endocrinogenesis in zebrafish and mouse early postnatal ducts and induced β-cell-specific genes in human adult duct-derived organoids. We also defined genomic sites that are bound and repressed by REST in the embryonic pancreas. Our findings show that REST-dependent inhibition ensures a balanced production of endocrine cells from embryonic pancreatic progenitors.
Rovira M, Maestro MA, Grau V, et al., 2021, Hnf1b-CreER causes efficient recombination of a Rosa26-RFP reporter in duct and islet delta cells, ISLETS, Vol: 13, Pages: 134-139, ISSN: 1938-2014
Bevacqua RJ, Dai X, Lam JY, et al., 2021, CRISPR-based genome editing in primary human pancreatic islet cells, NATURE COMMUNICATIONS, Vol: 12
Akerman I, Maestro MA, De Franco E, et al., 2021, Neonatal diabetes mutations disrupt a chromatin pioneering function that activates the human insulin gene, CELL REPORTS, Vol: 35, ISSN: 2211-1247
Bizzotto R, Jennison C, Jones AG, et al., 2021, Processes Underlying Glycemic Deterioration in Type 2 Diabetes: An IMI DIRECT Study, DIABETES CARE, Vol: 44, Pages: 511-518, ISSN: 0149-5992
Wessel J, Majarian TD, Highland HM, et al., 2020, Rare Non-coding Variation Identified by Large Scale Whole Genome Sequencing Reveals Unexplained Heritability of Type 2 Diabetes
<jats:p>Type 2 diabetes is increasing in all ancestry groups<jats:sup>1</jats:sup>. Part of its genetic basis may reside among the rare (minor allele frequency <0.1%) variants that make up the vast majority of human genetic variation<jats:sup>2</jats:sup>. We analyzed high-coverage (mean depth 38.2x) whole genome sequencing from 9,639 individuals with T2D and 34,994 controls in the NHLBI’s Trans-Omics for Precision Medicine (TOPMed) program<jats:sup>2</jats:sup> to show that rare, non-coding variants that are poorly captured by genotyping arrays or imputation panels contribute h<jats:sup>2</jats:sup>=53% (P=4.2×10<jats:sup>−5</jats:sup>) to the genetic component of risk in the largest (European) ancestry subset. We coupled sequence variation with islet epigenomic signatures<jats:sup>3</jats:sup> to annotate and group rare variants with respect to gene expression<jats:sup>4</jats:sup>, chromatin state<jats:sup>5</jats:sup> and three-dimensional chromatin architecture<jats:sup>6</jats:sup>, and show that pancreatic islet regulatory elements contribute to T2D genetic risk (h<jats:sup>2</jats:sup>=8%, P=2.4×10<jats:sup>−3</jats:sup>). We used islet annotation to create a non-coding framework for rare variant aggregation testing. This approach identified five loci containing rare alleles in islet regulatory elements that suggest novel biological mechanisms readily linked to hypotheses about variant-to-function. Large scale whole genome sequence analysis reveals the substantial contribution of rare, non-coding variation to the genetic architecture of T2D and highlights the value of tissue-specific regulatory annotation for variant-to-function discovery.</jats:p>
Bar N, Korem T, Weissbrod O, et al., 2020, A reference map of potential determinants for the human serum metabolome, NATURE, Vol: 588, Pages: 135-140, ISSN: 0028-0836
Mahajan A, Spracklen CN, Zhang W, et al., 2020, Trans-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation
<jats:title>ABSTRACT</jats:title><jats:p>We assembled an ancestrally diverse collection of genome-wide association studies of type 2 diabetes (T2D) in 180,834 cases and 1,159,055 controls (48.9% non-European descent). We identified 277 loci at genome-wide significance (<jats:italic>p</jats:italic><5×10<jats:sup>-8</jats:sup>), including 237 attaining a more stringent trans-ancestry threshold (<jats:italic>p</jats:italic><5×10<jats:sup>-9</jats:sup>), which were delineated to 338 distinct association signals. Trans-ancestry meta-regression offered substantial enhancements to fine-mapping, with 58.6% of associations more precisely localised due to population diversity, and 54.4% of signals resolved to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying foundations for functional investigations. Trans-ancestry genetic risk scores enhanced transferability across diverse populations, providing a step towards more effective clinical translation to improve global health.</jats:p>
Akerman I, Maestro MA, Grau V, et al., 2020, Neonatal diabetes mutations disrupt a chromatin pioneering function that activates the human insulin gene
<jats:title>ABSTRACT</jats:title><jats:p>Despite the central role of chromosomal context in gene transcription, human noncoding DNA variants are generally studied outside of their endogenous genomic location. This poses major limitations to understand the true consequences of causal regulatory variants. We focused on a cis-regulatory mutation (c.-331C>G) in the <jats:italic>INS</jats:italic> gene promoter that is recurrently mutated in unrelated patients with recessive neonatal diabetes. We created mice in which a ~3.1 kb human <jats:italic>INS</jats:italic> upstream region carrying −331C or −331G alleles replaced the orthologous mouse <jats:italic>Ins2</jats:italic> region. This human sequence drove cell-specific transcription in mice. It also recapitulated poised chromatin during pancreas development and active chromatin in differentiated β-cells. The c.-331C>G mutation, however, blocked active chromatin formation in differentiated b-cells. We further show that another neonatal diabetes gene product, GLIS3, had a singular pioneer-like ability to activate <jats:italic>INS</jats:italic> chromatin in non-pancreatic cells, which was hampered by the c.-331C>G mutation. This <jats:italic>in vivo</jats:italic> analysis of human regulatory defects, therefore, uncovered <jats:italic>cis</jats:italic> and <jats:italic>trans</jats:italic> components of a mechanism that is essential to activate the endogenous <jats:italic>INS</jats:italic> gene.</jats:p>
Kalisz M, Bernardo E, Beucher A, et al., 2020, HNF1A recruits KDM6A to activate differentiated acinar cell programs that suppress pancreatic cancer, The EMBO Journal, Vol: 39, ISSN: 0261-4189
Defects in transcriptional regulators of pancreatic exocrine differentiation have been implicated in pancreatic tumorigenesis, but the molecular mechanisms are poorly understood. The locus encoding the transcription factor HNF1A harbors susceptibility variants for pancreatic ductal adenocarcinoma (PDAC), while KDM6A, encoding Lysine-specific demethylase 6A, carries somatic mutations in PDAC. Here, we show that pancreas-specific Hnf1a null mutant transcriptomes phenocopy those of Kdm6a mutations, and both defects synergize with KrasG12D to cause PDAC with sarcomatoid features. We combine genetic, epigenomic, and biochemical studies to show that HNF1A recruits KDM6A to genomic binding sites in pancreatic acinar cells. This remodels the acinar enhancer landscape, activates differentiated acinar cell programs, and indirectly suppresses oncogenic and epithelial-mesenchymal transition genes. We also identify a subset of non-classical PDAC samples that exhibit the HNF1A/KDM6A-deficient molecular phenotype. These findings provide direct genetic evidence that HNF1A deficiency promotes PDAC. They also connect the tumor-suppressive role of KDM6A deficiency with a cell-specific molecular mechanism that underlies PDAC subtype definition.
Palomer X, Silvia Roman-Azcona M, Pizarro-Delgado J, et al., 2020, SIRT3-mediated inhibition of FOS through histone H3 deacetylation prevents cardiac fibrosis and inflammation, Signal Transduction and Targeted Therapy, Vol: 5, Pages: 1-10, ISSN: 2095-9907
Sirtuin 3 (SIRT3) is a deacetylase that modulates proteins that control metabolism and protects against oxidative stress. Modulation of SIRT3 activity has been proposed as a promising therapeutic target for ameliorating metabolic diseases and associated cardiac disturbances. In this study, we investigated the role of SIRT3 in inflammation and fibrosis in the heart using male mice with constitutive and systemic deletion of SIRT3 and human cardiac AC16 cells. SIRT3 knockout mice showed cardiac fibrosis and inflammation that was characterized by augmented transcriptional activity of AP-1. Consistent with this, SIRT3 overexpression in human and neonatal rat cardiomyocytes partially prevented the inflammatory and profibrotic response induced by TNF-α. Notably, these effects were associated with a decrease in the mRNA and protein levels of FOS and the DNA-binding activity of AP-1. Finally, we demonstrated that SIRT3 inhibits FOS transcription through specific histone H3 lysine K27 deacetylation at its promoter. These findings highlight an important function of SIRT3 in mediating the often intricate profibrotic and proinflammatory responses of cardiac cells through the modulation of the FOS/AP-1 pathway. Since fibrosis and inflammation are crucial in the progression of cardiac hypertrophy, heart failure, and diabetic cardiomyopathy, our results point to SIRT3 as a potential target for treating these diseases.
Baeyens L, Lemper M, Leuckx G, et al., 2020, Transient cytokine treatment induces acinar cell reprogramming and regenerates functional beta cell mass in diabetic mice (Retraction of Vol 32, Pg 76, 2019), NATURE BIOTECHNOLOGY, Vol: 38, Pages: 374-374, ISSN: 1087-0156
Wilman HR, Parisinos CA, Atabaki-Pasdar N, et al., 2019, Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration, Journal of Hepatology, Vol: 71, Pages: 594-602, ISSN: 0168-8278
BACKGROUND & AIMS: Excess liver iron content is common and is linked to the risk of hepatic and extrahepatic diseases. We aimed to identify genetic variants influencing liver iron content and use genetics to understand its link to other traits and diseases. METHODS: First, we performed a genome-wide association study (GWAS) in 8,289 individuals from UK Biobank, whose liver iron level had been quantified by magnetic resonance imaging, before validating our findings in an independent cohort (n = 1,513 from IMI DIRECT). Second, we used Mendelian randomisation to test the causal effects of 25 predominantly metabolic traits on liver iron content. Third, we tested phenome-wide associations between liver iron variants and 770 traits and disease outcomes. RESULTS: We identified 3 independent genetic variants (rs1800562 [C282Y] and rs1799945 [H63D] in HFE and rs855791 [V736A] in TMPRSS6) associated with liver iron content that reached the GWAS significance threshold (p <5 × 10-8). The 2 HFE variants account for ∼85% of all cases of hereditary haemochromatosis. Mendelian randomisation analysis provided evidence that higher central obesity plays a causal role in increased liver iron content. Phenome-wide association analysis demonstrated shared aetiopathogenic mechanisms for elevated liver iron, high blood pressure, cirrhosis, malignancies, neuropsychiatric and rheumatological conditions, while also highlighting inverse associations with anaemias, lipidaemias and ischaemic heart disease. CONCLUSION: Our study provides genetic evidence that mechanisms underlying higher liver iron content are likely systemic rather than organ specific, that higher central obesity is causally associated with higher liver iron, and that liver iron shares common aetiology with multiple metabolic and non-metabolic diseases. LAY SUMMARY: Excess liver iron content is common and is associated with liver diseases and metabolic diseases including diabetes, high blood pressure, and heart
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 SLC29A4) and Organic Cation Transporter 1 (OCT1) (Encoded by SLC22A1) and Gastrointestinal Intolerance to Metformin in Type 2 Diabetes: An IMI DIRECT Study, DIABETES CARE, Vol: 42, Pages: 1027-1033, ISSN: 0149-5992
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, Publisher: Cold Spring Harbor Laboratory
<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>
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