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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134 results found

Ferrer J, Dimitrova N, 2024, Transcription regulation by long non-coding RNAs: mechanisms and disease relevance., Nat Rev Mol Cell Biol

Long non-coding RNAs (lncRNAs) outnumber protein-coding transcripts, but their functions remain largely unknown. In this Review, we discuss the emerging roles of lncRNAs in the control of gene transcription. Some of the best characterized lncRNAs have essential transcription cis-regulatory functions that cannot be easily accomplished by DNA-interacting transcription factors, such as XIST, which controls X-chromosome inactivation, or imprinted lncRNAs that direct allele-specific repression. A growing number of lncRNA transcription units, including CHASERR, PVT1 and HASTER (also known as HNF1A-AS1) act as transcription-stabilizing elements that fine-tune the activity of dosage-sensitive genes that encode transcription factors. Genetic experiments have shown that defects in such transcription stabilizers often cause severe phenotypes. Other lncRNAs, such as lincRNA-p21 (also known as Trp53cor1) and Maenli (Gm29348) contribute to local activation of gene transcription, whereas distinct lncRNAs influence gene transcription in trans. We discuss findings of lncRNAs that elicit a function through either activation of their transcription, transcript elongation and processing or the lncRNA molecule itself. We also discuss emerging evidence of lncRNA involvement in human diseases, and their potential as therapeutic targets.

Journal article

Braun T, Sosnovski KE, Amir A, BenShoshan M, VanDussen KL, Karns R, Levhar N, Abbas-Egbariya H, Hadar R, Efroni G, Castel D, Avivi C, Rosen MJ, Grifiths AM, Walters TD, Mack DR, Boyle BM, Ali SA, Moore SR, Schirmer M, Xavier RJ, Kugathasan S, Jegga AG, Weiss B, Mayer C, Barshack I, Ben-Horin S, Ulitsky I, Beucher A, Ferrer J, Hyams JS, Denson LA, Haberman Yet al., 2023, Mucosal transcriptomics highlight lncRNAs implicated in ulcerative colitis, Crohn's disease, and celiac disease, JCI INSIGHT, Vol: 8

Journal article

Walters R, Vasilaki E, Aman J, Chen C-N, Wu Y, Liang OD, Ashek A, Dubois O, Zhao L, Sabrin F, Cebola I, Ferrer J, Morrell NW, Klinger JR, Wilkins MR, Zhao L, Rhodes CJet al., 2023, SOX17 enhancer variants disrupt transcription factor binding and enhancer inactivity drives pulmonary hypertension, Circulation, Vol: 147, Pages: 1606-1621, ISSN: 0009-7322

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease characterized by remodeling of the pulmonary arteries, increased vascular resistance, and right-sided heart failure. Genome-wide association studies of idiopathic/heritable PAH established novel genetic risk variants, including conserved enhancers upstream of transcription factor (TF) SOX17 containing 2 independent signals. SOX17 is an important TF in embryonic development and in the homeostasis of pulmonary artery endothelial cells (hPAEC) in the adult. Rare pathogenic mutations in SOX17 cause heritable PAH. We hypothesized that PAH risk alleles in an enhancer region impair TF-binding upstream of SOX17, which in turn reduces SOX17 expression and contributes to disturbed endothelial cell function and PAH development. METHODS: CRISPR manipulation and siRNA were used to modulate SOX17 expression. Electromobility shift assays were used to confirm in silico-predicted TF differential binding to the SOX17 variants. Functional assays in hPAECs were used to establish the biological consequences of SOX17 loss. In silico analysis with the connectivity map was used to predict compounds that rescue disturbed SOX17 signaling. Mice with deletion of the SOX17-signal 1 enhancer region (SOX17-4593/enhKO) were phenotyped in response to chronic hypoxia and SU5416/hypoxia. RESULTS: CRISPR inhibition of SOX17-signal 2 and deletion of SOX17-signal 1 specifically decreased SOX17 expression. Electromobility shift assays demonstrated differential binding of hPAEC nuclear proteins to the risk and nonrisk alleles from both SOX17 signals. Candidate TFs HOXA5 and ROR-α were identified through in silico analysis and antibody electromobility shift assays. Analysis of the hPAEC transcriptomes revealed alteration of PAH-relevant pathways on SOX17 silencing, including extracellular matrix regulation. SOX17 silencing in hPAECs resulted in increased apoptosis, proliferation, and disturbance of barrier function. With the use of t

Journal article

Nagao M, Fukuda A, Omatsu M, Namikawa M, Sono M, Fukunaga Y, Masuda T, Araki O, Yoshikawa T, Ogawa S, Masuo K, Goto N, Hiramatsu Y, Muta Y, Tsuda M, Maruno T, Nakanishi Y, Taketo MM, Ferrer J, Tsuruyama T, Nakanuma Y, Taura K, Uemoto S, Seno Het al., 2023, Concurrent Activation of Kras and Canonical Wnt Signaling Induces Premalignant Lesions That Progress to Extrahepatic Biliary Cancer in Mice, CANCER RESEARCH, Vol: 82, Pages: 1803-1817, ISSN: 0008-5472

Journal article

De Vas M, Boulet F, Joshi SS, Garstang MG, Khan TN, Atla G, Parry D, Moore D, Cebola I, Zhang S, Cui W, Lampe AK, Lam WW, Genomics England Research Consortium, Ferrer J, Madapura PM, Atanur SSet al., 2023, Regulatory de novo mutations underlying intellectual disability, Life Science Alliance, Vol: 6, Pages: 1-16, ISSN: 2575-1077

The genetic aetiology of a major fraction of patients with intellectual disability (ID) remains unknown. De novo mutations (DNMs) in protein-coding genes explain up to 40% of cases, but the potential role of regulatory DNMs is still poorly understood. We sequenced 63 whole genomes from 21 ID probands and their unaffected parents. In addition, we analysed 30 previously sequenced genomes from exome-negative ID probands. We found that regulatory DNMs were selectively enriched in fetal brain-specific enhancers as compared with adult brain enhancers. DNM-containing enhancers were associated with genes that show preferential expression in the prefrontal cortex. Furthermore, we identified recurrently mutated enhancer clusters that regulate genes involved in nervous system development (CSMD1, OLFM1, and POU3F3). Most of the DNMs from ID probands showed allele-specific enhancer activity when tested using luciferase assay. Using CRISPR-mediated mutation and editing of epigenomic marks, we show that DNMs at regulatory elements affect the expression of putative target genes. Our results, therefore, provide new evidence to indicate that DNMs in fetal brain-specific enhancers play an essential role in the aetiology of ID.

Journal article

Magenheim J, Maestro MA, Sharon N, Herrera PL, Murtaugh LC, Kopp J, Sander M, Gu G, Melton DA, Ferrer J, Dor Yet al., 2023, Matters arising: Insufficient evidence that pancreatic b cells are derived from adult ductal Neurog3-expressing progenitors, CELL STEM CELL, Vol: 30, Pages: 488-+, ISSN: 1934-5909

Journal article

Costanzo MC, von Grotthuss M, Massung J, Jang D, Caulkins L, Koesterer R, Gilbert C, Welch RP, Kudtarkar P, Hoang Q, Boughton AP, Singh P, Sun Y, Duby M, Moriondo A, Nguyen T, Smadbeck P, Alexander BR, Brandes M, Carmichael M, Dornbos P, Green T, Huellas-Bruskiewicz KC, Ji Y, Kluge A, McMahon AC, Mercader JM, Ruebenacker O, Sengupta S, Spalding D, Taliun D, AMP-T2D Consortium, Smith P, Thomas MK, Akolkar B, Brosnan MJ, Cherkas A, Chu AY, Fauman EB, Fox CS, Kamphaus TN, Miller MR, Nguyen L, Parsa A, Reilly DF, Ruetten H, Wholley D, Zaghloul NA, Abecasis GR, Altshuler D, Keane TM, McCarthy MI, Gaulton KJ, Florez JC, Boehnke M, Burtt NP, Flannick Jet al., 2023, The Type 2 Diabetes Knowledge Portal: an open access genetic resource dedicated to type 2 diabetes and related traits, Cell Metabolism, Vol: 35, Pages: 695-710.e6, ISSN: 1550-4131

Associations between human genetic variation and clinical phenotypes have become a foundation of biomedical research. Most repositories of these data seek to be disease-agnostic and therefore lack disease-focused views. The Type 2 Diabetes Knowledge Portal (T2DKP) is a public resource of genetic datasets and genomic annotations dedicated to type 2 diabetes (T2D) and related traits. Here, we seek to make the T2DKP more accessible to prospective users and more useful to existing users. First, we evaluate the T2DKP's comprehensiveness by comparing its datasets with those of other repositories. Second, we describe how researchers unfamiliar with human genetic data can begin using and correctly interpreting them via the T2DKP. Third, we describe how existing users can extend their current workflows to use the full suite of tools offered by the T2DKP. We finally discuss the lessons offered by the T2DKP toward the goal of democratizing access to complex disease genetic results.

Journal article

Allesoe RL, Lundgaard AT, Medina RH, Aguayo-Orozco A, Johansen J, Nissen JN, Brorsson C, Mazzoni G, Niu L, Biel JH, Brasas V, Webel H, Benros ME, Pedersen AG, Chmura PJ, Jacobsen UP, Mari A, Koivula R, Mahajan A, Vinuela A, Tajes JF, Sharma S, Haid M, Hong M-G, Musholt PB, De Masi F, Vogt J, Pedersen HK, Gudmundsdottir V, Jones A, Kennedy G, Bell J, Thomas EL, Frost G, Thomsen H, Hansen E, Hansen TH, Vestergaard H, Muilwijk M, Blom MT, Hart LMT, Pattou F, Raverdy V, Brage S, Kokkola T, Heggie A, McEvoy D, Mourby M, Kaye J, Hattersley A, McDonald T, Ridderstrale M, Walker M, Forgie I, Giordano GN, Pavo I, Ruetten H, Pedersen O, Hansen T, Dermitzakis E, Franks PW, Schwenk JM, Adamski J, McCarthy M, Pearson E, Banasik K, Rasmussen S, Brunak Set al., 2023, Discovery of drug-omics associations in type 2 diabetes with generative deep-learning models, NATURE BIOTECHNOLOGY, Vol: 41, Pages: 399-+, ISSN: 1087-0156

Journal article

Juan-Mateu J, Bajew S, Miret-Cuesta M, iniguez LP, Lopez-Pascual A, Bonnal S, Atla G, Bonas-Guarch S, Ferrer J, Valcarcel J, Irimia Met al., 2023, Pancreatic microexons regulate islet function and glucose homeostasis, NATURE METABOLISM, Vol: 5, Pages: 219-+

Journal article

Zaugg JB, Sahlen P, Andersson R, Alberich-Jorda M, de Laat W, Deplancke B, Ferrer J, Mandrup S, Natoli G, Plewczynski D, Rada-Iglesias A, Spicuglia Set al., 2022, Current challenges in understanding the role of enhancers in disease, NATURE STRUCTURAL & MOLECULAR BIOLOGY, Vol: 29, Pages: 1148-1158, ISSN: 1545-9993

Journal article

Beucher A, Miguel Escalada I, Balboa D, De Vas M, Maestro MA, Garcia-Hurtado J, Bernal A, Gonzalez Franco R, Vargiu P, Heyn H, Ravassard P, Ortega S, Ferrer Jet al., 2022, HASTER lncRNA promoter is a cis-acting transcriptional stabilizer of HNF1A, Nature Cell Biology, Vol: 24, Pages: 1528-1540, ISSN: 1465-7392

The biological purpose of long non-coding RNAs (lncRNAs) is poorly understood. Haploinsufficient mutations in HNF1A homeobox A (HNF1A), encoding a homeodomain transcription factor, cause diabetes mellitus. Here, we examine HASTER, the promoter of an 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 hyperglycaemia. 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, it 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.

Journal article

Atla G, Bonas-Guarch S, Cuenca-Ardura M, Beucher A, Crouch DJM, Garcia-Hurtado J, Moran I, the T2DSystems Consortium, Irimia M, Prasad RB, Gloyn AL, Marselli L, Suleiman M, Berney T, de Koning EJP, Kerr-Conte J, Pattou F, Todd JA, Piemonti L, Ferrer Jet al., 2022, Genetic regulation of RNA splicing in human pancreatic islets, Genome Biology, Vol: 23, Pages: 1-28, 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.

Journal article

Cuenca-Ardura M, De Vas M, Balboa D, Ferrer Jet al., 2022, Genome-wide CRISPR screens identify therapeutic targets for HNF1A-deficient diabetes, Publisher: SPRINGER, Pages: S162-S162, ISSN: 0012-186X

Conference paper

Miguel-Escalada I, Maestro MÁ, Balboa D, Elek A, Bernal A, Bernardo E, Grau V, García-Hurtado J, Sebé-Pedrós A, Ferrer Jet 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.

Journal article

Fukunaga Y, Fukuda A, Omatsu M, Namikawa M, Sono M, Masuda T, Araki O, Nagao M, Yoshikawa T, Ogawa S, Hiramatsu Y, Muta Y, Tsuda M, Maruno T, Nakanishi Y, Ferrer J, Tsuruyama T, Masui T, Hatano E, Seno Het al., 2022, Loss of Arid1a and Pten in Pancreatic Ductal Cells Induces Intraductal Tubulopapillary Neoplasm via the YAP/TAZ Pathway, GASTROENTEROLOGY, Vol: 163, Pages: 466-+, ISSN: 0016-5085

Journal article

Mahajan A, Spracklen CN, Zhang W, Ng MCY, Petty LE, Kitajima H, Yu GZ, Rueger 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, Parolo PDB, 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, Prins BP, Nicolas A, Yanek LR, Chen G, Jensen RA, Tajuddin S, Kabagambe EK, An P, Xiang AH, Choi HS, Cade BE, Tan J, Flanagan 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 B, Fuchsberger C, Genter P, Gerstein HC, Giedraitis V, Gonzalez-Villalpando C, Gonzalez-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, Jorgensen ME, Jorgensen 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, Lall 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 KR, Meitinet 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

Journal article

Alonso L, Piron A, Moran I, Guindo-Martinez M, Bonas-Guarch S, Atla G, Miguel-Escalada I, Royo R, Puiggros M, Garcia-Hurtado X, Suleiman M, Marselli L, Esguerra JLS, Turatsinze J-V, Torres JM, Nylander V, Chen J, Eliasson L, Defrance M, Amela R, Mulder H, Gloyn AL, Groop L, Marchetti P, Eizirik DL, Ferrer J, Mercader JM, Cnop M, Torrents Det al., 2021, TIGER: The gene expression regulatory variation landscape of human pancreatic islets, CELL REPORTS, Vol: 37, ISSN: 2211-1247

Journal article

Rovira M, Maestro MA, Grau V, Ferrer Jet al., 2021, <i>Hnf1b</i>-CreER causes efficient recombination of a Rosa26-RFP reporter in duct and islet δ cells, ISLETS, Vol: 13, Pages: 134-139, ISSN: 1938-2014

Journal article

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, 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.

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

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

Akerman I, Maestro MA, Grau V, García-Hurtado J, Mittler G, Ravassard P, Piemonti L, Ferrer Jet al., 2021, Neonatal diabetes mutations disrupt a chromatin pioneering function that activates the human insulin gene, Cell Reports, ISSN: 2211-1247

<h4>ABSTRACT</h4> 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 INS gene promoter that is recurrently mutated in unrelated patients with recessive neonatal diabetes. We created mice in which a ~3.1 kb human INS upstream region carrying −331C or −331G alleles replaced the orthologous mouse Ins2 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 INS chromatin in non-pancreatic cells, which was hampered by the c.-331C>G mutation. This in vivo analysis of human regulatory defects, therefore, uncovered cis and trans components of a mechanism that is essential to activate the endogenous INS gene.

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

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

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

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

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

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

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

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

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