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Organogenesis and functional genomics of the endocrine pancreas

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Abstract

Functional genomics, the analysis of the wealth of data produced by genome-wide analyses of gene expression, protein–protein, and protein–DNA interactions, has revolutionized biomedical research. Our ability to determine global gene expression profiles, transcription factor-binding sites, and histone modification maps using microarray-based technologies and next-generation sequencing applications has greatly enhanced our understanding of gene regulatory networks and the molecular wiring diagrams of cells and tissues. The organogenesis of the endocrine pancreas involves numerous signaling events within the endoderm-derived pancreatic epithelium and the surrounding mesenchyme, as well as complex transcription factor networks. Detailed understanding of the differentiation process from foregut endoderm to mature endocrine cells has enabled the rational design of in vitro differentiation protocols that coax embryonic stem cells into β-like cells that might enable cell replacement therapy for diabetes in the future. In this review, we summarize the research studies that have utilized genomic tools to elucidate endocrine pancreatic organogenesis.

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References

  1. D’Adamo E, Caprio S (2011) Type 2 diabetes in youth: epidemiology and pathophysiology. Diabetes Care 34(Suppl 2):S161–S165. doi:10.2337/dc11-s212

    Article  PubMed  Google Scholar 

  2. Shaw JE, Sicree RA, Zimmet PZ (2010) Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract 87(1):4–14. doi:10.1016/j.diabres.2009.10.007

    Article  CAS  PubMed  Google Scholar 

  3. Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL, Kneteman NM, Rajotte RV (2000) Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 343(4):230–238. doi:10.1056/NEJM200007273430401

    Article  CAS  PubMed  Google Scholar 

  4. Vehik K, Dabelea D (2011) The changing epidemiology of type 1 diabetes: why is it going through the roof? Diabetes Metab Res Rev 27(1):3–13. doi:10.1002/dmrr.1141

    Article  PubMed  Google Scholar 

  5. D’Amour KA, Bang AG, Eliazer S, Kelly OG, Agulnick AD, Smart NG, Moorman MA, Kroon E, Carpenter MK, Baetge EE (2006) Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nat Biotechnol 24(11):1392–1401. doi:10.1038/nbt1259

    Article  PubMed  CAS  Google Scholar 

  6. Kroon E, Martinson LA, Kadoya K, Bang AG, Kelly OG, Eliazer S, Young H, Richardson M, Smart NG, Cunningham J, Agulnick AD, D’Amour KA, Carpenter MK, Baetge EE (2008) Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotechnol 26(4):443–452. doi:10.1038/nbt1393

    Article  CAS  PubMed  Google Scholar 

  7. McKusick VA (1997) Genomics: structural and functional studies of genomes. Genomics 45(2):244–249

    Article  CAS  PubMed  Google Scholar 

  8. Rastan S, Beeley LJ (1997) Functional genomics: going forwards from the databases. Curr Opin Genet Dev 7(6):777–783

    Article  CAS  PubMed  Google Scholar 

  9. Brown PO, Botstein D (1999) Exploring the new world of the genome with DNA microarrays. Nat Genet 21(1 Suppl):33–37. doi:10.1038/4462

    Article  CAS  PubMed  Google Scholar 

  10. Bulyk ML (2006) DNA microarray technologies for measuring protein-DNA interactions. Curr Opin Biotechnol 17(4):422–430. doi:10.1016/j.copbio.2006.06.015

    Article  CAS  PubMed  Google Scholar 

  11. Eisen MB, Spellman PT, Brown PO, Botstein D (1998) Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci USA 95(25):14863–14868

    Article  CAS  PubMed  Google Scholar 

  12. Mardis ER (2007) ChIP-seq: welcome to the new frontier. Nat Methods 4(8):613–614. doi:10.1038/nmeth0807-613

    Article  CAS  PubMed  Google Scholar 

  13. Wang Z, Gerstein M, Snyder M (2009) RNA-Seq: a revolutionary tool for transcriptomics. Nat Rev Genet 10(1):57–63. doi:10.1038/nrg2484

    Article  CAS  PubMed  Google Scholar 

  14. Oliver-Krasinski JM, Stoffers DA (2008) On the origin of the beta cell. Genes Dev 22(15):1998–2021. doi:10.1101/gad.1670808

    Article  CAS  PubMed  Google Scholar 

  15. Pesce M, Scholer HR (2001) Oct-4: gatekeeper in the beginnings of mammalian development. Stem Cells 19(4):271–278. doi:10.1634/stemcells.19-4-271

    Article  CAS  PubMed  Google Scholar 

  16. Lee TI, Young RA (2000) Transcription of eukaryotic protein-coding genes. Annu Rev Genet 34:77–137. doi:10.1146/annurev.genet.34.1.77

    Article  CAS  PubMed  Google Scholar 

  17. Park PJ (2009) ChIP-seq: advantages and challenges of a maturing technology. Nat Rev Genet 10(10):669–680. doi:10.1038/nrg2641

    Article  CAS  PubMed  Google Scholar 

  18. Bhandare R, Schug J, Le Lay J, Fox A, Smirnova O, Liu C, Naji A, Kaestner KH (2010) Genome-wide analysis of histone modifications in human pancreatic islets. Genome Res 20(4):428–433. doi:10.1101/gr.102038.109

    Article  CAS  PubMed  Google Scholar 

  19. van Arensbergen J, Garcia-Hurtado J, Moran I, Maestro MA, Xu X, Van de Casteele M, Skoudy AL, Palassini M, Heimberg H, Ferrer J (2010) Derepression of Polycomb targets during pancreatic organogenesis allows insulin-producing beta-cells to adopt a neural gene activity program. Genome Res 20(6):722–732. doi:10.1101/gr.101709.109

    Article  PubMed  CAS  Google Scholar 

  20. Le Douarin NM (1988) On the origin of pancreatic endocrine cells. Cell 53(2):169–171

    Article  PubMed  Google Scholar 

  21. Slack JM (1995) Developmental biology of the pancreas. Development 121(6):1569–1580

    CAS  PubMed  Google Scholar 

  22. Hebrok M, Kim SK, Melton DA (1998) Notochord repression of endodermal Sonic hedgehog permits pancreas development. Genes Dev 12(11):1705–1713

    Article  CAS  PubMed  Google Scholar 

  23. Yoshitomi H, Zaret KS (2004) Endothelial cell interactions initiate dorsal pancreas development by selectively inducing the transcription factor Ptf1a. Development 131(4):807–817. doi:10.1242/dev.00960

    Article  CAS  PubMed  Google Scholar 

  24. Jacquemin P, Yoshitomi H, Kashima Y, Rousseau GG, Lemaigre FP, Zaret KS (2006) An endothelial-mesenchymal relay pathway regulates early phases of pancreas development. Dev Biol 290(1):189–199. doi:10.1016/j.ydbio.2005.11.023

    Article  CAS  PubMed  Google Scholar 

  25. Bort R, Martinez-Barbera JP, Beddington RS, Zaret KS (2004) Hex homeobox gene-dependent tissue positioning is required for organogenesis of the ventral pancreas. Development 131(4):797–806. doi:10.1242/dev.00965

    Article  CAS  PubMed  Google Scholar 

  26. Martin M, Gallego-Llamas J, Ribes V, Kedinger M, Niederreither K, Chambon P, Dolle P, Gradwohl G (2005) Dorsal pancreas agenesis in retinoic acid-deficient Raldh2 mutant mice. Dev Biol 284(2):399–411. doi:10.1016/j.ydbio.2005.05.035

    Article  CAS  PubMed  Google Scholar 

  27. Wandzioch E, Zaret KS (2009) Dynamic signaling network for the specification of embryonic pancreas and liver progenitors. Science 324(5935):1707–1710. doi:10.1126/science.1174497

    Article  CAS  PubMed  Google Scholar 

  28. Pictet RL, Clark WR, Williams RH, Rutter WJ (1972) An ultrastructural analysis of the developing embryonic pancreas. Dev Biol 29(4):436–467

    Article  CAS  PubMed  Google Scholar 

  29. Herrera PL, Huarte J, Sanvito F, Meda P, Orci L, Vassalli JD (1991) Embryogenesis of the murine endocrine pancreas; early expression of pancreatic polypeptide gene. Development 113(4):1257–1265

    CAS  PubMed  Google Scholar 

  30. Herrera PL (2000) Adult insulin- and glucagon-producing cells differentiate from two independent cell lineages. Development 127(11):2317–2322

    CAS  PubMed  Google Scholar 

  31. Prado CL, Pugh-Bernard AE, Elghazi L, Sosa-Pineda B, Sussel L (2004) Ghrelin cells replace insulin-producing beta cells in two mouse models of pancreas development. Proc Natl Acad Sci USA 101(9):2924–2929. doi:10.1073/pnas.0308604100

    Article  CAS  PubMed  Google Scholar 

  32. Pictet R, Rutter W (1972) Development of embryonic endocrine pancreas. In: Steiner DF, Feinkel N (eds) Handbook of physiology. Washington, DC

    Google Scholar 

  33. Johansson KA, Dursun U, Jordan N, Gu G, Beermann F, Gradwohl G, Grapin-Botton A (2007) Temporal control of neurogenin3 activity in pancreas progenitors reveals competence windows for the generation of different endocrine cell types. Dev Cell 12(3):457–465. doi:10.1016/j.devcel.2007.02.010

    Article  CAS  PubMed  Google Scholar 

  34. Zhou Q, Law AC, Rajagopal J, Anderson WJ, Gray PA, Melton DA (2007) A multipotent progenitor domain guides pancreatic organogenesis. Dev Cell 13(1):103–114. doi:10.1016/j.devcel.2007.06.001

    Article  CAS  PubMed  Google Scholar 

  35. Miller K, Kim A, Kilimnik G, Jo J, Moka U, Periwal V, Hara M (2009) Islet formation during the neonatal development in mice. PLoS One 4(11):e7739. doi:10.1371/journal.pone.0007739

    Article  PubMed  CAS  Google Scholar 

  36. Gu G, Dubauskaite J, Melton DA (2002) Direct evidence for the pancreatic lineage: NGN3+ cells are islet progenitors and are distinct from duct progenitors. Development 129(10):2447–2457

    CAS  PubMed  Google Scholar 

  37. Gradwohl G, Dierich A, LeMeur M, Guillemot F (2000) Neurogenin3 is required for the development of the four endocrine cell lineages of the pancreas. Proc Natl Acad Sci USA 97(4):1607–1611

    Article  CAS  PubMed  Google Scholar 

  38. Ahlgren U, Jonsson J, Edlund H (1996) The morphogenesis of the pancreatic mesenchyme is uncoupled from that of the pancreatic epithelium in IPF1/PDX1-deficient mice. Development 122(5):1409–1416

    CAS  PubMed  Google Scholar 

  39. Offield MF, Jetton TL, Labosky PA, Ray M, Stein RW, Magnuson MA, Hogan BL, Wright CV (1996) PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. Development 122(3):983–995

    CAS  PubMed  Google Scholar 

  40. Stoffers DA, Heller RS, Miller CP, Habener JF (1999) Developmental expression of the homeodomain protein IDX-1 in mice transgenic for an IDX-1 promoter/lacZ transcriptional reporter. Endocrinology 140(11):5374–5381

    Article  CAS  PubMed  Google Scholar 

  41. Krapp A, Knofler M, Ledermann B, Burki K, Berney C, Zoerkler N, Hagenbuchle O, Wellauer PK (1998) The bHLH protein PTF1-p48 is essential for the formation of the exocrine and the correct spatial organization of the endocrine pancreas. Genes Dev 12(23):3752–3763

    Article  CAS  PubMed  Google Scholar 

  42. Smith SB, Qu HQ, Taleb N, Kishimoto NY, Scheel DW, Lu Y, Patch AM, Grabs R, Wang J, Lynn FC, Miyatsuka T, Mitchell J, Seerke R, Desir J, Eijnden SV, Abramowicz M, Kacet N, Weill J, Renard ME, Gentile M, Hansen I, Dewar K, Hattersley AT, Wang R, Wilson ME, Johnson JD, Polychronakos C, German MS (2010) Rfx6 directs islet formation and insulin production in mice and humans. Nature 463(7282):775–780. doi:10.1038/nature08748

    Article  CAS  PubMed  Google Scholar 

  43. Kaestner KH, Katz J, Liu Y, Drucker DJ, Schutz G (1999) Inactivation of the winged helix transcription factor HNF3alpha affects glucose homeostasis and islet glucagon gene expression in vivo. Genes Dev 13(4):495–504

    Article  CAS  PubMed  Google Scholar 

  44. Shih DQ, Navas MA, Kuwajima S, Duncan SA, Stoffel M (1999) Impaired glucose homeostasis and neonatal mortality in hepatocyte nuclear factor 3alpha-deficient mice. Proc Natl Acad Sci USA 96(18):10152–10157

    Article  CAS  PubMed  Google Scholar 

  45. Lantz KA, Vatamaniuk MZ, Brestelli JE, Friedman JR, Matschinsky FM, Kaestner KH (2004) Foxa2 regulates multiple pathways of insulin secretion. J Clin Invest 114(4):512–520. doi:10.1172/JCI21149

    CAS  PubMed  Google Scholar 

  46. Sund NJ, Vatamaniuk MZ, Casey M, Ang SL, Magnuson MA, Stoffers DA, Matschinsky FM, Kaestner KH (2001) Tissue-specific deletion of Foxa2 in pancreatic beta cells results in hyperinsulinemic hypoglycemia. Genes Dev 15(13):1706–1715. doi:10.1101/gad.901601

    Article  CAS  PubMed  Google Scholar 

  47. Sussel L, Kalamaras J, Hartigan-O’Connor DJ, Meneses JJ, Pedersen RA, Rubenstein JL, German MS (1998) Mice lacking the homeodomain transcription factor Nkx2.2 have diabetes due to arrested differentiation of pancreatic beta cells. Development 125(12):2213–2221

    CAS  PubMed  Google Scholar 

  48. Henseleit KD, Nelson SB, Kuhlbrodt K, Hennings JC, Ericson J, Sander M (2005) NKX6 transcription factor activity is required for alpha- and beta-cell development in the pancreas. Development 132(13):3139–3149. doi:10.1242/dev.01875

    Article  CAS  PubMed  Google Scholar 

  49. Sander M, Sussel L, Conners J, Scheel D, Kalamaras J, Dela Cruz F, Schwitzgebel V, Hayes-Jordan A, German M (2000) Homeobox gene Nkx6.1 lies downstream of Nkx2.2 in the major pathway of beta-cell formation in the pancreas. Development 127(24):5533–5540

    CAS  PubMed  Google Scholar 

  50. Soyer J, Flasse L, Raffelsberger W, Beucher A, Orvain C, Peers B, Ravassard P, Vermot J, Voz ML, Mellitzer G, Gradwohl G (2010) Rfx6 is an Ngn3-dependent winged helix transcription factor required for pancreatic islet cell development. Development 137(2):203–212. doi:10.1242/dev.041673

    Article  CAS  PubMed  Google Scholar 

  51. Wang S, Jensen JN, Seymour PA, Hsu W, Dor Y, Sander M, Magnuson MA, Serup P, Gu G (2009) Sustained Neurog3 expression in hormone-expressing islet cells is required for endocrine maturation and function. Proc Natl Acad Sci USA 106(24):9715–9720. doi:10.1073/pnas.0904247106

    Article  CAS  PubMed  Google Scholar 

  52. Ren B, Robert F, Wyrick JJ, Aparicio O, Jennings EG, Simon I, Zeitlinger J, Schreiber J, Hannett N, Kanin E, Volkert TL, Wilson CJ, Bell SP, Young RA (2000) Genome-wide location and function of DNA binding proteins. Science 290(5500):2306–2309. doi:10.1126/science.290.5500.2306

    Article  CAS  PubMed  Google Scholar 

  53. Metzker ML (2010) Sequencing technologies—the next generation. Nat Rev Genet 11(1):31–46. doi:10.1038/nrg2626

    Article  CAS  PubMed  Google Scholar 

  54. Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z, Wei G, Chepelev I, Zhao K (2007) High-resolution profiling of histone methylations in the human genome. Cell 129(4):823–837. doi:10.1016/j.cell.2007.05.009

    Article  CAS  PubMed  Google Scholar 

  55. Johnson DS, Mortazavi A, Myers RM, Wold B (2007) Genome-wide mapping of in vivo protein-DNA interactions. Science 316(5830):1497–1502. doi:10.1126/science.1141319

    Article  CAS  PubMed  Google Scholar 

  56. Ji H, Jiang H, Ma W, Johnson DS, Myers RM, Wong WH (2008) An integrated software system for analyzing ChIP-chip and ChIP-seq data. Nat Biotechnol 26(11):1293–1300. doi:10.1038/nbt.1505

    Article  CAS  PubMed  Google Scholar 

  57. Zhang Y, Liu T, Meyer CA, Eeckhoute J, Johnson DS, Bernstein BE, Nusbaum C, Myers RM, Brown M, Li W, Liu XS (2008) Model-based analysis of ChIP-Seq (MACS). Genome Biol 9(9):R137. doi:10.1186/gb-2008-9-9-r137

    Article  PubMed  CAS  Google Scholar 

  58. Rozowsky J, Euskirchen G, Auerbach RK, Zhang ZD, Gibson T, Bjornson R, Carriero N, Snyder M, Gerstein MB (2009) PeakSeq enables systematic scoring of ChIP-seq experiments relative to controls. Nat Biotechnol 27(1):66–75. doi:10.1038/nbt.1518

    Article  CAS  PubMed  Google Scholar 

  59. Valouev A, Johnson DS, Sundquist A, Medina C, Anton E, Batzoglou S, Myers RM, Sidow A (2008) Genome-wide analysis of transcription factor binding sites based on ChIP-Seq data. Nat Methods 5(9):829–834. doi:10.1038/nmeth.1246

    Article  CAS  PubMed  Google Scholar 

  60. Tuteja G, White P, Schug J, Kaestner KH (2009) Extracting transcription factor targets from ChIP-Seq data. Nucleic Acids Res 37(17):e113. doi:10.1093/nar/gkp536

    Article  PubMed  CAS  Google Scholar 

  61. Lin YC, Jhunjhunwala S, Benner C, Heinz S, Welinder E, Mansson R, Sigvardsson M, Hagman J, Espinoza CA, Dutkowski J, Ideker T, Glass CK, Murre C (2010) A global network of transcription factors, involving E2A, EBF1 and Foxo1, that orchestrates B cell fate. Nat Immunol 11(7):635–643. doi:10.1038/ni.1891

    Article  CAS  PubMed  Google Scholar 

  62. Heinz S, Benner C, Spann N, Bertolino E, Lin YC, Laslo P, Cheng JX, Murre C, Singh H, Glass CK (2010) Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell 38(4):576–589. doi:10.1016/j.molcel.2010.05.004

    Article  CAS  PubMed  Google Scholar 

  63. Pepke S, Wold B, Mortazavi A (2009) Computation for ChIP-seq and RNA-seq studies. Nat Methods 6(11 Suppl):S22–S32. doi:10.1038/nmeth.1371

    Article  CAS  PubMed  Google Scholar 

  64. Rye MB, Saetrom P, Drablos F (2011) A manually curated ChIP-seq benchmark demonstrates room for improvement in current peak-finder programs. Nucleic Acids Res 39(4):e25. doi:10.1093/nar/gkq1187

    Article  PubMed  CAS  Google Scholar 

  65. Ellis L, Atadja PW, Johnstone RW (2009) Epigenetics in cancer: targeting chromatin modifications. Mol Cancer Ther 8(6):1409–1420. doi:10.1158/1535-7163.MCT-08-0860

    Article  CAS  PubMed  Google Scholar 

  66. Tsai HC, Baylin SB (2011) Cancer epigenetics: linking basic biology to clinical medicine. Cell Res 21(3):502–517. doi:10.1038/cr.2011.24

    Article  CAS  PubMed  Google Scholar 

  67. Haumaitre C, Lenoir O, Scharfmann R (2008) Histone deacetylase inhibitors modify pancreatic cell fate determination and amplify endocrine progenitors. Mol Cell Biol 28(20):6373–6383. doi:10.1128/MCB.00413-08

    Article  CAS  PubMed  Google Scholar 

  68. Haumaitre C, Lenoir O, Scharfmann R (2009) Directing cell differentiation with small-molecule histone deacetylase inhibitors: the example of promoting pancreatic endocrine cells. Cell Cycle 8(4):536–544

    Article  CAS  PubMed  Google Scholar 

  69. Nagalakshmi U, Wang Z, Waern K, Shou C, Raha D, Gerstein M, Snyder M (2008) The transcriptional landscape of the yeast genome defined by RNA sequencing. Science 320(5881):1344–1349. doi:10.1126/science.1158441

    Article  CAS  PubMed  Google Scholar 

  70. Cloonan N, Forrest AR, Kolle G, Gardiner BB, Faulkner GJ, Brown MK, Taylor DF, Steptoe AL, Wani S, Bethel G, Robertson AJ, Perkins AC, Bruce SJ, Lee CC, Ranade SS, Peckham HE, Manning JM, McKernan KJ, Grimmond SM (2008) Stem cell transcriptome profiling via massive-scale mRNA sequencing. Nat Methods 5(7):613–619. doi:10.1038/nmeth.1223

    Article  CAS  PubMed  Google Scholar 

  71. Mortazavi A, Williams BA, McCue K, Schaeffer L, Wold B (2008) Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat Methods 5(7):621–628. doi:10.1038/nmeth.1226

    Article  CAS  PubMed  Google Scholar 

  72. Marioni JC, Mason CE, Mane SM, Stephens M, Gilad Y (2008) RNA-seq: an assessment of technical reproducibility and comparison with gene expression arrays. Genome Res 18(9):1509–1517. doi:10.1101/gr.079558.108

    Article  CAS  PubMed  Google Scholar 

  73. Soukas A, Cohen P, Socci ND, Friedman JM (2000) Leptin-specific patterns of gene expression in white adipose tissue. Genes Dev 14(8):963–980

    CAS  PubMed  Google Scholar 

  74. Zimmer Y, Milo-Landesman D, Svetlanov A, Efrat S (1999) Genes induced by growth arrest in a pancreatic beta cell line: identification by analysis of cDNA arrays. FEBS Lett 457(1):65–70

    Article  CAS  PubMed  Google Scholar 

  75. Cardozo AK, Kruhoffer M, Leeman R, Orntoft T, Eizirik DL (2001) Identification of novel cytokine-induced genes in pancreatic beta-cells by high-density oligonucleotide arrays. Diabetes 50(5):909–920

    Article  CAS  PubMed  Google Scholar 

  76. Scearce LM, Brestelli JE, McWeeney SK, Lee CS, Mazzarelli J, Pinney DF, Pizarro A, Stoeckert CJ Jr, Clifton SW, Permutt MA, Brown J, Melton DA, Kaestner KH (2002) Functional genomics of the endocrine pancreas: the pancreas clone set and PancChip, new resources for diabetes research. Diabetes 51(7):1997–2004

    Article  CAS  PubMed  Google Scholar 

  77. Kaestner KH, Lee CS, Scearce LM, Brestelli JE, Arsenlis A, Le PP, Lantz KA, Crabtree J, Pizarro A, Mazzarelli J, Pinney D, Fischer S, Manduchi E, Stoeckert CJ Jr, Gradwohl G, Clifton SW, Brown JR, Inoue H, Cras-Meneur C, Permutt MA (2003) Transcriptional program of the endocrine pancreas in mice and humans. Diabetes 52(7):1604–1610

    Article  CAS  PubMed  Google Scholar 

  78. Jonsson J, Ahlgren U, Edlund T, Edlund H (1995) IPF1, a homeodomain protein with a dual function in pancreas development. Int J Dev Biol 39(5):789–798

    CAS  PubMed  Google Scholar 

  79. Ahlgren U, Jonsson J, Jonsson L, Simu K, Edlund H (1998) beta-cell-specific inactivation of the mouse Ipf1/Pdx1 gene results in loss of the beta-cell phenotype and maturity onset diabetes. Genes Dev 12(12):1763–1768

    Article  CAS  PubMed  Google Scholar 

  80. Stoffers DA, Ferrer J, Clarke WL, Habener JF (1997) Early-onset type-II diabetes mellitus (MODY4) linked to IPF1. Nat Genet 17(2):138–139. doi:10.1038/ng1097-138

    Article  CAS  PubMed  Google Scholar 

  81. Stoffers DA, Zinkin NT, Stanojevic V, Clarke WL, Habener JF (1997) Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat Genet 15(1):106–110. doi:10.1038/ng0197-106

    Article  CAS  PubMed  Google Scholar 

  82. Chiang MK, Melton DA (2003) Single-cell transcript analysis of pancreas development. Dev Cell 4(3):383–393

    Article  CAS  PubMed  Google Scholar 

  83. Gu G, Wells JM, Dombkowski D, Preffer F, Aronow B, Melton DA (2004) Global expression analysis of gene regulatory pathways during endocrine pancreatic development. Development 131(1):165–179. doi:10.1242/dev.00921

    Article  CAS  PubMed  Google Scholar 

  84. Svensson P, Williams C, Lundeberg J, Ryden P, Bergqvist I, Edlund H (2007) Gene array identification of Ipf1/Pdx1-/- regulated genes in pancreatic progenitor cells. BMC Dev Biol 7:129. doi:10.1186/1471-213X-7-129

    Article  PubMed  CAS  Google Scholar 

  85. Sachdeva MM, Claiborn KC, Khoo C, Yang J, Groff DN, Mirmira RG, Stoffers DA (2009) Pdx1 (MODY4) regulates pancreatic beta cell susceptibility to ER stress. Proc Natl Acad Sci USA 106(45):19090–19095. doi:10.1073/pnas.0904849106

    Article  CAS  PubMed  Google Scholar 

  86. Keller DM, McWeeney S, Arsenlis A, Drouin J, Wright CV, Wang H, Wollheim CB, White P, Kaestner KH, Goodman RH (2007) Characterization of pancreatic transcription factor Pdx-1 binding sites using promoter microarray and serial analysis of chromatin occupancy. J Biol Chem 282(44):32084–32092. doi:10.1074/jbc.M700899200

    Article  CAS  PubMed  Google Scholar 

  87. Poy MN, Eliasson L, Krutzfeldt J, Kuwajima S, Ma X, Macdonald PE, Pfeffer S, Tuschl T, Rajewsky N, Rorsman P, Stoffel M (2004) A pancreatic islet-specific microRNA regulates insulin secretion. Nature 432(7014):226–230. doi:10.1038/nature03076

    Article  CAS  PubMed  Google Scholar 

  88. Poy MN, Hausser J, Trajkovski M, Braun M, Collins S, Rorsman P, Zavolan M, Stoffel M (2009) miR-375 maintains normal pancreatic alpha- and beta-cell mass. Proc Natl Acad Sci USA 106(14):5813–5818. doi:10.1073/pnas.0810550106

    Article  CAS  PubMed  Google Scholar 

  89. Melkman-Zehavi T, Oren R, Kredo-Russo S, Shapira T, Mandelbaum AD, Rivkin N, Nir T, Lennox KA, Behlke MA, Dor Y, Hornstein E (2011) miRNAs control insulin content in pancreatic beta-cells via downregulation of transcriptional repressors. EMBO J 30(5):835–845. doi:10.1038/emboj.2010.361

    Article  CAS  PubMed  Google Scholar 

  90. Petri A, Ahnfelt-Ronne J, Frederiksen KS, Edwards DG, Madsen D, Serup P, Fleckner J, Heller RS (2006) The effect of neurogenin3 deficiency on pancreatic gene expression in embryonic mice. J Mol Endocrinol 37(2):301–316. doi:10.1677/jme.1.02096

    Article  CAS  PubMed  Google Scholar 

  91. Juhl K, Sarkar SA, Wong R, Jensen J, Hutton JC (2008) Mouse pancreatic endocrine cell transcriptome defined in the embryonic Ngn3-null mouse. Diabetes 57(10):2755–2761. doi:10.2337/db07-1126

    Article  CAS  PubMed  Google Scholar 

  92. White P, May CL, Lamounier RN, Brestelli JE, Kaestner KH (2008) Defining pancreatic endocrine precursors and their descendants. Diabetes 57(3):654–668. doi:10.2337/db07-1362

    Article  CAS  PubMed  Google Scholar 

  93. Gunton JE, Kulkarni RN, Yim S, Okada T, Hawthorne WJ, Tseng YH, Roberson RS, Ricordi C, O’Connell PJ, Gonzalez FJ, Kahn CR (2005) Loss of ARNT/HIF1beta mediates altered gene expression and pancreatic-islet dysfunction in human type 2 diabetes. Cell 122(3):337–349. doi:10.1016/j.cell.2005.05.027

    Article  CAS  PubMed  Google Scholar 

  94. Gupta RK, Gao N, Gorski RK, White P, Hardy OT, Rafiq K, Brestelli JE, Chen G, Stoeckert CJ Jr, Kaestner KH (2007) Expansion of adult beta-cell mass in response to increased metabolic demand is dependent on HNF-4alpha. Genes Dev 21(7):756–769. doi:10.1101/gad.1535507

    Article  CAS  PubMed  Google Scholar 

  95. Friedman JR, Kaestner KH (2006) The Foxa family of transcription factors in development and metabolism. Cell Mol Life Sci 63(19–20):2317–2328. doi:10.1007/s00018-006-6095-6

    Article  CAS  PubMed  Google Scholar 

  96. Gao N, White P, Doliba N, Golson ML, Matschinsky FM, Kaestner KH (2007) Foxa2 controls vesicle docking and insulin secretion in mature Beta cells. Cell Metab 6(4):267–279. doi:10.1016/j.cmet.2007.08.015

    Article  CAS  PubMed  Google Scholar 

  97. Gao N, Le Lay J, Qin W, Doliba N, Schug J, Fox AJ, Smirnova O, Matschinsky FM, Kaestner KH (2010) Foxa1 and Foxa2 maintain the metabolic and secretory features of the mature beta-cell. Mol Endocrinol 24(8):1594–1604. doi:10.1210/me.2009-0513

    Article  CAS  PubMed  Google Scholar 

  98. Gao N, LeLay J, Vatamaniuk MZ, Rieck S, Friedman JR, Kaestner KH (2008) Dynamic regulation of Pdx1 enhancers by Foxa1 and Foxa2 is essential for pancreas development. Genes Dev 22(24):3435–3448. doi:10.1101/gad.1752608

    Article  CAS  PubMed  Google Scholar 

  99. Anderson KR, White P, Kaestner KH, Sussel L (2009) Identification of known and novel pancreas genes expressed downstream of Nkx2.2 during development. BMC Dev Biol 9:65. doi:10.1186/1471-213X-9-65

    Article  PubMed  CAS  Google Scholar 

  100. Artner I, Hang Y, Mazur M, Yamamoto T, Guo M, Lindner J, Magnuson MA, Stein R (2010) MafA and MafB regulate genes critical to beta-cells in a unique temporal manner. Diabetes 59(10):2530–2539. doi:10.2337/db10-0190

    Article  CAS  PubMed  Google Scholar 

  101. Naya FJ, Huang HP, Qiu Y, Mutoh H, DeMayo FJ, Leiter AB, Tsai MJ (1997) Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BETA2/neuroD-deficient mice. Genes Dev 11(18):2323–2334

    Article  CAS  PubMed  Google Scholar 

  102. Gu C, Stein GH, Pan N, Goebbels S, Hornberg H, Nave KA, Herrera P, White P, Kaestner KH, Sussel L, Lee JE (2010) Pancreatic beta cells require NeuroD to achieve and maintain functional maturity. Cell Metab 11(4):298–310. doi:10.1016/j.cmet.2010.03.006

    Article  CAS  PubMed  Google Scholar 

  103. Wang P, Rodriguez RT, Wang J, Ghodasara A, Kim SK (2011) Targeting SOX17 in human embryonic stem cells creates unique strategies for isolating and analyzing developing endoderm. Cell Stem Cell 8(3):335–346. doi:10.1016/j.stem.2011.01.017

    Article  PubMed  CAS  Google Scholar 

  104. Kutlu B, Burdick D, Baxter D, Rasschaert J, Flamez D, Eizirik DL, Welsh N, Goodman N, Hood L (2009) Detailed transcriptome atlas of the pancreatic beta cell. BMC Med Genomics 2:3. doi:10.1186/1755-8794-2-3

    Article  PubMed  CAS  Google Scholar 

  105. Martens GA, Jiang L, Hellemans KH, Stange G, Heimberg H, Nielsen FC, Sand O, Van Helden J, Gorus FK, Pipeleers DG (2011) Clusters of conserved beta cell marker genes for assessment of beta cell phenotype. PLoS One 6(9):e24134. doi:10.1371/journal.pone.0024134

    Article  CAS  PubMed  Google Scholar 

  106. Dorrell C, Schug J, Lin CF, Canaday PS, Fox AJ, Smirnova O, Bonnah R, Streeter PR, Stoeckert CJ Jr, Kaestner KH, Grompe M (2011) Transcriptomes of the major human pancreatic cell types. Diabetologia 54(11):2832–2844. doi:10.1007/s00125-011-2283-5

    Article  CAS  PubMed  Google Scholar 

  107. Bernstein BE, Meissner A, Lander ES (2007) The mammalian epigenome. Cell 128(4):669–681. doi:10.1016/j.cell.2007.01.033

    Article  CAS  PubMed  Google Scholar 

  108. Li B, Carey M, Workman JL (2007) The role of chromatin during transcription. Cell 128(4):707–719. doi:10.1016/j.cell.2007.01.015

    Article  CAS  PubMed  Google Scholar 

  109. Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ, Cuff J, Fry B, Meissner A, Wernig M, Plath K, Jaenisch R, Wagschal A, Feil R, Schreiber SL, Lander ES (2006) A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125(2):315–326. doi:10.1016/j.cell.2006.02.041

    Article  CAS  PubMed  Google Scholar 

  110. Pan G, Tian S, Nie J, Yang C, Ruotti V, Wei H, Jonsdottir GA, Stewart R, Thomson JA (2007) Whole-genome analysis of histone H3 lysine 4 and lysine 27 methylation in human embryonic stem cells. Cell Stem Cell 1(3):299–312. doi:10.1016/j.stem.2007.08.003

    Article  CAS  PubMed  Google Scholar 

  111. 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 J (2010) A map of open chromatin in human pancreatic islets. Nat Genet 42(3):255–259. doi:10.1038/ng.530

    Article  CAS  PubMed  Google Scholar 

  112. Stitzel ML, Sethupathy P, Pearson DS, Chines PS, Song L, Erdos MR, Welch R, Parker SC, Boyle AP, Scott LJ, Margulies EH, Boehnke M, Furey TS, Crawford GE, Collins FS (2010) Global epigenomic analysis of primary human pancreatic islets provides insights into type 2 diabetes susceptibility loci. Cell Metab 12(5):443–455. doi:10.1016/j.cmet.2010.09.012

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Amber Riblett for careful copy-editing of the manuscript. Related work in the Kaestner lab has been supported through NIH grants DK088383, DK055342, and DK089529.

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  1. Department of Genetics, Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, 12-126 Translational Research Center, 3400 Civic Center Boulevard, Philadelphia, PA, 19104, USA

    Nuria C. Bramswig & Klaus H. Kaestner

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  1. Nuria C. Bramswig
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  2. Klaus H. Kaestner
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Correspondence to Klaus H. Kaestner.

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Bramswig, N.C., Kaestner, K.H. Organogenesis and functional genomics of the endocrine pancreas. Cell. Mol. Life Sci. 69, 2109–2123 (2012). https://doi.org/10.1007/s00018-011-0915-z

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  • DOI: https://doi.org/10.1007/s00018-011-0915-z

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