Imperial College London

ProfessorJorgeFerrer

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Chair in Medicine and Genetics
 
 
 
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Contact

 

+44 (0)20 7594 0968j.ferrer

 
 
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Location

 

535ICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
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117 results found

Rovira M, Atla G, Maestro MA, Grau V, García-Hurtado J, Maqueda M, Mosquera JL, Yamada Y, Kerr-Conte J, Pattou F, Ferrer Jet al., 2021, REST is a major negative regulator of endocrine differentiation during pancreas organogenesis, Genes & Development, 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.

Journal article

Rovira M, Maestro MA, Grau V, Ferrer Jet al., 2021, Hnf1b-CreER causes efficient recombination of a Rosa26-RFP reporter in duct and islet delta cells, ISLETS, ISSN: 1938-2014

Journal article

Bevacqua RJ, Dai X, Lam JY, Gu X, Friedlander MSH, Tellez K, Miguel-Escalada I, Bonas-Guarch S, Atla G, Zhao W, Kim SH, Dominguez AA, Qi LS, Ferrer J, MacDonald PE, Kim SKet al., 2021, CRISPR-based genome editing in primary human pancreatic islet cells, NATURE COMMUNICATIONS, Vol: 12, ISSN: 2041-1723

Journal article

Akerman I, Maestro MA, De Franco E, Grau V, Flanagan S, Garcia-Hurtado J, Mittler G, Ravassard P, Piemonti L, Ellard S, Hattersley AT, Ferrer Jet al., 2021, Neonatal diabetes mutations disrupt a chromatin pioneering function that activates the human insulin gene, CELL REPORTS, Vol: 35, ISSN: 2211-1247

Journal article

Bizzotto R, Jennison C, Jones AG, Kurbasic A, Tura A, Kennedy G, Bell JD, Thomas EL, Frost G, Eriksen R, Koivula RW, Brage S, Kaye J, Hattersley AT, Heggie A, McEvoy D, 't Hart LM, Beulens JW, Elders P, Musholt PB, Ridderstrale M, Hansen TH, Allin KH, Hansen T, Vestergaard H, Lundgaard AT, Thomsen HS, De Masi F, Tsirigos KD, Brunak S, Vinuela A, Mahajan A, McDonald TJ, Kokkola T, Forgie IM, Giordano GN, Pavo I, Ruetten H, Dermitzakis E, McCarthy MI, Pedersen O, Schwenk JM, Adamski J, Franks PW, Walker M, Pearson ER, Mari Aet al., 2021, Processes Underlying Glycemic Deterioration in Type 2 Diabetes: An IMI DIRECT Study, DIABETES CARE, Vol: 44, Pages: 511-518, ISSN: 0149-5992

Journal article

Wessel J, Majarian TD, Highland HM, Raghavan S, Szeto MD, Hasbani NR, de Vries PS, Brody JA, Sarnowski C, DiCorpo D, Yin X, Hidalgo B, Guo X, Perry J, OConnell JR, Lent S, Montasser ME, Cade BE, Jain D, Wang H, Wu P, Bonàs-Guarch S, DOliveira Albanus R, Leong A, Miguel-Escalada I, Varshney A, Kinney GL, Yanek LR, Lange L, Almeida M, Peralta JM, Aslibekyan S, Baldridge AS, Bertoni AG, Bielak LF, Bowden DW, Chen C-S, Chen Y-DI, Choi SH, Choi WJ, Darbar D, Floyd JS, Freedman BI, Goodarzi MO, Irvin R, Kalyani RR, Kelly T, Lee S, Liu C-T, Loesch D, Manson JE, Nassir R, Palmer ND, Pankow JS, Rasmussen-Torvik LJ, Reiner AP, Selvin E, Shadyab AH, Smith JA, Weeks DE, Weng L-C, Xu H, Yao J, Yoneda Z, Zhao W, Ferrer J, Mahajan A, McCarthy MI, Parker S, Alonso A, Arnett DK, Blangero J, Boerwinkle E, Cho MH, Correa A, Cupples LA, Curran JE, Duggirala R, Ellinor PT, He J, Heckbert SR, Kardia SLR, Kim RW, Kooperberg C, Liu S, Lubitz SA, Mathias RA, McGarvey S, Mitchell BD, Morrison AC, Peyser PA, Psaty BM, Redline S, Roden D, Shoemaker MB, Smith NL, Taylor KD, Vasan RS, Viaud-Martinez KA, Florez JC, Wilson JG, Sladek R, Dupuis J, Rich SS, Rotter JI, Meigs JB, Manning AKet 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 &lt;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>

Journal article

Bar N, Korem T, Weissbrod O, Zeevi D, Rothschild D, Leviatan S, Kosower N, Lotan-Pompan M, Weinberger A, Le Roy CI, Menni C, Visconti A, Falchi M, Spector TD, Adamski J, Franks PW, Pedersen O, Segal Eet al., 2020, A reference map of potential determinants for the human serum metabolome, NATURE, Vol: 588, Pages: 135-140, ISSN: 0028-0836

Journal article

Mahajan A, Spracklen CN, Zhang W, Ng MCY, Petty LE, Kitajima H, Yu GZ, Rüeger S, Speidel L, Kim YJ, Horikoshi M, Mercader JM, Taliun D, Moon S, Kwak S-H, Robertson NR, Rayner NW, Loh M, Kim B-J, Chiou J, Miguel-Escalada I, Briotta Parolo PD, Lin K, Bragg F, Preuss MH, Takeuchi F, Nano J, Guo X, Lamri A, Nakatochi M, Scott RA, Lee J-J, Huerta-Chagoya A, Graff M, Chai J-F, Parra EJ, Yao J, Bielak LF, Tabara Y, Hai Y, Steinthorsdottir V, Cook JP, Kals M, Grarup N, Schmidt EM, Pan I, Sofer T, Wuttke M, Sarnowski C, Gieger C, Nousome D, Trompet S, Long J, Sun M, Tong L, Chen W-M, Ahmad M, Noordam R, Lim VJY, Tam CHT, Joo YY, Chen C-H, Raffield LM, Lecoeur C, Maruthur NM, Prins BP, Nicolas A, Yanek LR, Chen G, Jensen RA, Tajuddin S, Kabagambe E, An P, Xiang AH, Choi HS, Cade BE, Tan J, Abaitua F, Adair LS, Adeyemo A, Aguilar-Salinas CA, Akiyama M, Anand SS, Bertoni A, Bian Z, Bork-Jensen J, Brandslund I, Brody JA, Brummett CM, Buchanan TA, Canouil M, Chan JCN, Chang L-C, Chee M-L, Chen J, Chen S-H, Chen Y-T, Chen Z, Chuang L-M, Cushman M, Das SK, de Silva HJ, Dedoussis G, Dimitrov L, Doumatey AP, Du S, Duan Q, Eckardt K-U, Emery LS, Evans DS, Evans MK, Fischer K, Floyd JS, Ford I, Fornage M, Franco OH, Frayling TM, Freedman BI, Fuchsberger C, Genter P, Gerstein HC, Giedraitis V, González-Villalpando C, González-Villalpando ME, Goodarzi MO, Gordon-Larsen P, Gorkin D, Gross M, Guo Y, Hackinger S, Han S, Hattersley AT, Herder C, Howard A-G, Hsueh W, Huang M, Huang W, Hung Y-J, Hwang MY, Hwu C-M, Ichihara S, Ikram MA, Ingelsson M, Islam MT, Isono M, Jang H-M, Jasmine F, Jiang G, Jonas JB, Jørgensen ME, Jørgensen T, Kamatani Y, Kandeel FR, Kasturiratne A, Katsuya T, Kaur V, Kawaguchi T, Keaton JM, Kho AN, Khor C-C, Kibriya MG, Kim D-H, Kohara K, Kriebel J, Kronenberg F, Kuusisto J, Läll K, Lange LA, Lee M-S, Lee NR, Leong A, Li L, Li Y, Li-Gao R, Ligthart S, Lindgren CM, Linneberg A, Liu C-T, Liu J, Locke AE, Louie T, Luan J, Luk AO, Luo X, Lv J, Lyssenko V, Mamakou V, Mani KRet 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>&lt;5×10<jats:sup>-8</jats:sup>), including 237 attaining a more stringent trans-ancestry threshold (<jats:italic>p</jats:italic>&lt;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 &gt;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>

Journal article

Akerman I, Maestro MA, Grau V, García-Hurtado J, Mittler G, Ravassard P, Piemonti L, Ferrer Jet 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&gt;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&gt;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&gt;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>

Journal article

Kalisz M, Bernardo E, Beucher A, Maestro MA, Del Pozo N, Millán I, Haeberle L, Schlensog M, Safi SA, Knoefel WT, Grau V, de Vas M, Shpargel KB, Vaquero E, Magnuson T, Ortega S, Esposito I, Real FX, Ferrer Jet 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.

Journal article

Palomer X, Silvia Roman-Azcona M, Pizarro-Delgado J, Planavila A, Villarroya F, Valenzuela-Alcaraz B, Crispi F, Sepulveda-Martinez A, Miguel-Escalada I, Ferrer J, Francisco Nistal J, Garcia R, Davidson MM, Barroso E, Vazquez-Carrera Met 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.

Journal article

Baeyens L, Lemper M, Leuckx G, De Groef S, Bonfanti P, Stange G, Shemer R, Nord C, Scheel DW, Pan FC, Ahlgren U, Gu G, Stoffers DA, Dor Y, Ferrer J, Gradwohl G, Wright CVE, Van de Casteele M, German MS, Bouwens L, Heimberg Het 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

Journal article

Wilman HR, Parisinos CA, Atabaki-Pasdar N, Kelly M, Thomas EL, Neubauer S, IMI DIRECT Consortium, Mahajan A, Hingorani AD, Patel RS, Hemingway H, Franks PW, Bell JD, Banerjee R, Yaghootkar Het 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

Journal article

Miguel-Escalada I, Bonàs-Guarch S, Cebola I, Ponsa-Cobas J, Mendieta-Esteban J, Atla G, Javierre BM, Rolando DMY, Farabella I, Morgan CC, Garcia-Hurtado J, Beucher A, Morán I, Pasquali L, Ramos-Rodríguez M, Appel EVR, Linneberg A, Gjesing AP, Witte DR, Pedersen O, Grarup N, Ravassard P, Torrents D, Mercader JM, Piemonti L, Berney T, de Koning EJP, Kerr-Conte J, Pattou F, Fedko IO, Groop L, Prokopenko I, Hansen T, Marti-Renom MA, Fraser P, Ferrer J, dos Santos Cebola Iet 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.

Journal article

Ferrer J, 2019, HNF1A recruits KDM6A to activate diffentiated acinar cell programs that suppress pancreatic cancer, The EMBO Journal, ISSN: 0261-4189

Journal article

Dawed AY, Zhou K, van Leeuwen N, Mahajan A, Robertson N, Koivula R, Elders PJM, Rauh SP, Jones AG, Holl RW, Stingl JC, Franks PW, McCarthy MI, 't Hart LM, Pearson ERet 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

Journal article

Kalna V, Yang Y, Peghaire C, Frudd K, hannah R, Shah A, Osuna Almagro L, Boyle J, gottgens B, Ferrer J, Randi A, Birdsey Get 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

Journal article

Rhodes CJ, Batai K, Bleda M, Haimel M, Southgate L, Germain M, Pauciulo MW, Hadinnapola C, Aman J, Girerd B, Arora A, Knight J, Hanscombe KB, Karnes JH, Kaakinen M, Gall H, Ulrich A, Harbaum L, Cebola I, Ferrer J, Lutz K, Swietlik EM, Ahmad F, Amouyel P, Archer SL, Argula R, Austin ED, Badesch D, Bakshi S, Barnett C, Benza R, Bhatt N, Bogaard HJ, Burger CD, Chakinala M, Church C, Coghlan JG, Condliffe R, Corris PA, Danesino C, Debette S, Elliott CG, Elwing J, Eyries M, Fortin T, Franke A, Frantz RP, Frost A, Garcia JGN, Ghio S, Ghofrani H-A, Gibbs JSR, Harley J, He H, Hill NS, Hirsch R, Houweling AC, Howard LS, Ivy D, Kiely DG, Klinger J, Kovacs G, Lahm T, Laudes M, Machado RD, Ross RVM, Marsolo K, Martin LJ, Moledina S, Montani D, Nathan SD, Newnham M, Olschewski A, Olschewski H, Oudiz RJ, Ouwehand WH, Peacock AJ, Pepke-Zaba J, Rehman Z, Robbins I, Roden DM, Rosenzweig EB, Saydain G, Scelsi L, Schilz R, Seeger W, Shaffer CM, Simms RW, Simon M, Sitbon O, Suntharalingam J, Tang H, Tchourbanov AY, Thenappan T, Torres F, Toshner MR, Treacy CM, Noordegraaf AV, Waisfisz Q, Walsworth AK, Walter RE, Wharton J, White RJ, Wilt J, Wort SJ, Yung D, Lawrie A, Humbert M, Soubrier F, Trégouët D-A, Prokopenko I, Kittles R, Gräf S, Nichols WC, Trembath RC, Desai AA, Morrell NW, Wilkins MR, UK NIHR BioResource Rare Diseases Consortium, UK PAH Cohort Study Consortium, US PAH Biobank Consortiumet 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

Journal article

Font-Cunill B, Arnes L, Ferrer J, Sussel L, Beucher A, Ferrer J, Beucher Aet 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.

Journal article

Miguel-Escalada I, Bonàs-Guarch S, Cebola I, Ponsa-Cobas J, Ferrer Jet 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.

Working paper

Millership S, Da Silva Xavier G, Choudhury A, Bertazzo S, Chabosseau PL, Pedroni SMA, Irvine E, Montoya A, Faull P, Taylor WR, Kerr-Conte J, Pattou F, Ferrer J, Christian M, John RM, Latreille M, Liu M, Rutter G, Scott J, Withers DJet 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.

Journal article

de Lichtenberg KH, Seymour PA, Jørgensen MC, Kim Y-H, Grapin-Botton A, Magnuson MA, Nakic N, Ferrer J, Serup Pet 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>

Working paper

de Lichtenberg KH, Funa N, Nakic N, Ferrer J, Zhu Z, Huangfu D, Serup Pet al., 2018, Genome-Wide Identification of HES1 Target Genes Uncover Novel Roles for HES1 in Pancreatic Development, Publisher: Cold Spring Harbor Laboratory

<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 int

Working paper

Bonas-Guarch S, Guindo-Martinez M, Miguel-Escalada I, Grarup N, Sebastian D, Rodriguez-Fos E, Sanchez F, Planas-Felix M, Cortes-Sanchez P, Gonzalez S, Timshel P, Pers TH, Morgan CC, Moran I, Atla G, Gonzalez JR, Puiggros M, Marti J, Andersson EA, Diaz C, Badia RM, Udler M, Leong A, Kaur V, Flannick J, Jorgensen T, Linneberg A, Jorgensen ME, Witte DR, Christensen C, Brandslund I, Appel EV, Scott RA, Luan J, Langenberg C, Wareham NJ, Pedersen O, Zorzano A, Florez JC, Hansen T, Ferrer J, Maria Mercader J, Torrents Det 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.

Journal article

Mereu E, Iacono G, Guillaumet-Adkins A, Moutinho C, Lunazzi G, Santos CP, Miguel-Escalada I, Ferrer J, Real FX, Gut I, Heyn Het al., 2018, matchSCore: Matching Single-Cell Phenotypes Across Tools and Experiments, Publisher: Cold Spring Harbor Laboratory

<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>

Working paper

Martinez-Sanchez A, Nguyen-Tu M-S, Cebola I, Yavari A, Marchetti P, Piemonti L, de Koning E, Shapiro AMJ, Johnson P, Sakamoto K, Smith DM, Leclerc I, Ashrafian H, Ferrer J, Rutter GA, Martinez-sanchez A, Nguyen-Tu M-S, Cebola I, Yavari A, Marchetti P, Piemonti L, de Koning E, Shapiro AMJ, Johnson P, Sakamoto K, Smith DM, Leclerc I, Ashrafian H, Ferrer J, Rutter GAet 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.

Journal article

Bonas-Guarch S, Guindo-Martinez M, Miguel-Escalada I, Grarup N, Sebastian D, Rodriguez-Fos E, Sanchez F, Planas-Felix M, Cortes-Sanchez P, Gonzalez S, Timshel P, Pers TH, Morgan CC, Moran I, Atla G, Gonzalez JR, Puiggros M, Marti J, Andersson EA, Diaz C, Badia RM, Udler M, Leong A, Kaur V, Flannick J, Jorgensen T, Linneberg A, Jorgensen ME, Witte DR, Christensen C, Brandslund I, Appel EV, Scott RA, Luan J, Langenberg C, Wareham NJ, Pedersen O, Zorzano A, Florez JC, Hansen T, Ferrer J, Maria Mercader J, Torrents Det 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.

Journal article

Gudmundsdottir V, Pedersen HK, Allebrandt KV, Brorsson C, van Leeuwen N, Banasik K, Mahajan A, Groves CJ, van de Bunt M, Dawed AY, Fritsche A, Staiger H, Simonis-Bik AMC, Deelen J, Kramer MHH, Dietrich A, Hübschle T, Willemsen G, Häring H-U, de Geus EJC, Boomsma DI, Eekhoff EMW, Ferrer J, McCarthy MI, Pearson ER, Gupta R, Brunak S, 't Hart LMet 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

Journal article

Mercader JM, Liao RG, Bell AD, Dymek Z, Estrada K, Tukiainen T, Huerta-Chagoya A, Moreno-Macias H, Jablonski KA, Hanson RL, Walford GA, Moran I, Chen L, Agarwala V, Luisa Ordonez-Sanchez M, Rodriguez-Guillen R, Rodriguez-Torres M, Segura-Kato Y, Garcia-Ortiz H, Centeno-Cruz F, Barajas-Olmos F, Caulkins L, Puppala S, Fontanillas P, Williams AL, Bonas-Guarch S, Hartl C, Ripke S, Tooley K, Lane J, Zerrweck C, Martinez-Hernandez A, Cordova EJ, Mendoza-Caamal E, Contreras-Cubas C, Gonzalez-Villalpando ME, Cruz-Bautista I, Munoz-Hernandez L, Gomez-Velasco D, Alvirde U, Henderson BE, Wilkens LR, Le Marchand L, Arellano-Campos O, Riba L, Harden M, Gabriel S, Abboud HE, Cortes ML, Revilla-Monsalve C, Islas-Andrade S, Soberon X, Curran JE, Jenkinson CP, DeFronzo RA, Lehman DM, Hanis CL, Bell GI, Boehnke M, Blangero J, Duggirala R, Saxena R, MacArthur D, Ferrer J, McCarroll SA, Torrents D, Knowler WC, Baier LJ, Burtt N, Gonzalez-Villalpando C, Haiman CA, Aguilar-Salinas CA, Tusie-Luna T, Flannick J, Jacobs SBR, Orozco L, Altshuler D, Florez JCet 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.

Journal article

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