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  • Journal article
    Rodriguez-Segui S, Akerman I, Ferrer J, 2012,

    GATA believe it: new essential regulators of pancreas development

    , JOURNAL OF CLINICAL INVESTIGATION, Vol: 122, Pages: 3469-3471, ISSN: 0021-9738
  • Journal article
    Moran I, Akerman I, van de Bunt M, Xie R, Benazra M, Nammo T, Arnes L, Nakic N, Garcia-Hurtado J, Rodriguez-Segui S, Pasquali L, Sauty-Colace C, Beucher A, Scharfmann R, van Arensbergen J, Johnson PR, Berry A, Lee C, Harkins T, Gmyr V, Pattou F, Kerr-Conte J, Piemonti L, Berney T, Hanley N, Gloyn AL, Sussel L, Langman L, Brayman KL, Sander M, McCarthy MI, Ravassard P, Ferrer Jet al., 2012,

    Human beta Cell Transcriptome Analysis Uncovers IncRNAs That Are Tissue-Specific, Dynamically Regulated, and Abnormally Expressed in Type 2 Diabetes

    , CELL METABOLISM, Vol: 16, Pages: 435-448, ISSN: 1550-4131
  • Journal article
    Swales N, Martens GA, Bonné S, Heremans Y, Borup R, Van de Casteele M, Ling Z, Pipeleers D, Ravassard P, Nielsen F, Ferrer J, Heimberg Het al., 2012,

    Plasticity of adult human pancreatic duct cells by neurogenin3-mediated reprogramming.

    , PLOS One, Vol: 7, Pages: e37055-e37055, ISSN: 1932-6203

    AIMS/HYPOTHESIS: Duct cells isolated from adult human pancreas can be reprogrammed to express islet beta cell genes by adenoviral transduction of the developmental transcription factor neurogenin3 (Ngn3). In this study we aimed to fully characterize the extent of this reprogramming and intended to improve it. METHODS: The extent of the Ngn3-mediated duct-to-endocrine cell reprogramming was measured employing genome wide mRNA profiling. By modulation of the Delta-Notch signaling or addition of pancreatic endocrine transcription factors Myt1, MafA and Pdx1 we intended to improve the reprogramming. RESULTS: Ngn3 stimulates duct cells to express a focused set of genes that are characteristic for islet endocrine cells and/or neural tissues. This neuro-endocrine shift however, is incomplete with less than 10% of full duct-to-endocrine reprogramming achieved. Transduction of exogenous Ngn3 activates endogenous Ngn3 suggesting auto-activation of this gene. Furthermore, pancreatic endocrine reprogramming of human duct cells can be moderately enhanced by inhibition of Delta-Notch signaling as well as by co-expressing the transcription factor Myt1, but not MafA and Pdx1. CONCLUSIONS/INTERPRETATION: The results provide further insight into the plasticity of adult human duct cells and suggest measurable routes to enhance Ngn3-mediated in vitro reprogramming protocols for regenerative beta cell therapy in diabetes.

  • Journal article
    Allen HL, Flanagan SE, Shaw-Smith C, De Franco E, Akerman I, Caswell R, Ferrer J, Hattersley AT, Ellard Set al., 2012,

    GATA6 haploinsufficiency causes pancreatic agenesis in humans

    , NATURE GENETICS, Vol: 44, Pages: 20-22, ISSN: 1061-4036
  • Journal article
    Kirkpatrick CL, Wiederkehr A, Baquie M, Akhmedov D, Wang H, Gauthier BR, Akerman I, Ishihara H, Ferrer J, Wollheim CBet al., 2011,

    Hepatic Nuclear Factor 1 alpha (HNF1 alpha) Dysfunction Down-regulates X-box-binding Protein 1 (XBP1) and Sensitizes beta-Cells to Endoplasmic Reticulum Stress

    , JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 286, Pages: 32300-32312
  • Journal article
    Nammo T, Rodriguez-Segui SA, Ferrer J, 2011,

    Mapping Open Chromatin with Formaldehyde-Assisted Isolation of Regulatory Elements

    , EPIGENETICS PROTOCOLS, SECOND EDITION, Vol: 791, Pages: 287-296, ISSN: 1064-3745
  • Journal article
    Gjesing AP, Larsen LH, Torekov SS, Hainerova IA, Kapur R, Johansen A, Albrechtsen A, Boj S, Holst B, Harper A, Urhammer SA, Borch-Johnsen K, Pisinger C, Echwald SM, Eiberg H, Astrup A, Lebl J, Ferrer J, Schwartz TW, Hansen T, Pedersen Oet al., 2010,

    Family and population-based studies of variation within the Ghrelin receptor locus in relation to measures of obesity

    , PLoS ONE, Vol: 5, ISSN: 1932-6203

    BackgroundThe growth hormone secretagogue receptor (GHSR) is mediating hunger sensation when stimulated by its natural ligand ghrelin. In the present study, we tested the hypothesis that common and rare variation in the GHSR locus are related to increased prevalence of obesity and overweight among Whites.Methodology/Principal FindingsIn a population-based study sample of 15,854 unrelated, middle-aged Danes, seven variants were genotyped to capture common variation in an 11 kbp region including GHSR. These were investigated for their individual and haplotypic association with obesity. None of these analyses revealed consistent association with measures of obesity. A -151C/T promoter mutation in the GHSR was found in two unrelated obese patients. One family presented with complete co-segregation, but the other with incomplete co-segregation. The mutation resulted in an increased transcriptional activity (p<0.02) and introduction of a specific binding for Sp-1-like nuclear extracts relative to the wild type. The -151C/T mutation was genotyped in the 15,854 Danes with a minor allele frequency of 0.01%. No association with obesity in carriers (mean BMI: 27±4 kg/m2) versus non-carriers (mean BMI: 28±5 kg/m2) (p>0.05) could be shown.Conclusions/SignificanceIn a population-based study sample of 15,854 Danes no association between GHSR genotypes and measures of obesity and overweight was found. Also, analyses of GHSR haplotypes lack consistent associations with obesity related traits. A rare functional GHSR promoter mutation variant was identified, yet there was no consistent relationship with obesity in neither family- nor population-based studies.

  • Journal article
    Gaulton KJ, Nammo T, Pasquali L, Simon JM, Giresi PG, Fogarty MP, Panhuis TM, Mieczkowski P, Secchi A, Bosco D, Berney T, Montanya E, Mohlke KL, Lieb JD, Ferrer Jet al., 2010,

    A map of open chromatin in human pancreatic islets

    , Nature Genetics, Vol: 42, Pages: 255-U41, ISSN: 1061-4036

    Tissue-specific transcriptional regulation is central to human disease1. To identify regulatory DNA active in human pancreatic islets, we profiled chromatin by formaldehyde-assisted isolation of regulatory elements2,3,4 coupled with high-throughput sequencing (FAIRE-seq). We identified ∼80,000 open chromatin sites. Comparison of FAIRE-seq data from islets to that from five non-islet cell lines revealed ∼3,300 physically linked clusters of islet-selective open chromatin sites, which typically encompassed single genes that have islet-specific expression. We mapped sequence variants to open chromatin sites and found that rs7903146, a TCF7L2 intronic variant strongly associated with type 2 diabetes5, is located in islet-selective open chromatin. We found that human islet samples heterozygous for rs7903146 showed allelic imbalance in islet FAIRE signals and that the variant alters enhancer activity, indicating that genetic variation at this locus acts in cis with local chromatin and regulatory changes. These findings illuminate the tissue-specific organization of cis-regulatory elements and show that FAIRE-seq can guide the identification of regulatory variants underlying disease susceptibility.

  • Journal article
    Garin I, Edghill EL, Akerman I, Rubio-Cabezas O, Rica I, Locke JM, Angel Maestro M, Alshaikh A, Bundak R, del Castillo G, Deeb A, Deiss D, Fernandez JM, Godbole K, Hussain K, O'Connell M, Klupa T, Kolouskova S, Mohsin F, Perlman K, Sumnik Z, Rial JM, Ugarte E, Vasanthi T, Johnstone K, Flanagan SE, Martinez R, Castano C, Patch A-M, Fernandez-Rebollo E, Raile K, Morgan N, Harries LW, Castano L, Ellard S, Ferrer J, Perez de Nanclares G, Hattersley ATet al., 2010,

    Recessive mutations in the INS gene result in neonatal diabetes through reduced insulin biosynthesis

    , PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 107, Pages: 3105-3110, ISSN: 0027-8424
  • Journal article
    Solar M, Cardalda C, Houbracken I, Martin M, Angel Maestro M, De Medts N, Xu X, Grau V, Heimberg H, Bouwens L, Ferrer Jet al., 2009,

    Pancreatic Exocrine Duct Cells Give Rise to Insulin-Producing beta Cells during Embryogenesis but Not after Birth

    , DEVELOPMENTAL CELL, Vol: 17, Pages: 849-860, ISSN: 1534-5807

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