The transcriptional landscape of mouse beta cells compared to human beta cells reveals notable species differences in long non-coding RNA and protein-coding gene expression

BMC Genomics

Mark O Huising³  Cynthia J Donaldson²  Kristof Tigyi²  Elena Cacéres²  Talitha van der Meulen²  Christopher Benner¹ 

[1] Razzavi Newman Integrated Genomics and Bioinformatics Core, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA;Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA;Present address: Department of Neurobiology, Physiology & Behavior, University of California, One Shields Avenue, 180 Briggs Hall, Davis, CA 95616, USA

关键词: Ets1;    Amylin;    Iapp;    Islet amyloid polypeptide;    Cntfr;    Ciliary neurotrophic factor receptor;    Ghr;    Growth hormone receptor;    Prlr;    Prolactin receptor;    RNA-seq;    lncRNA;    Diabetes;    Crh;    Ucn3;    Glucagon;    Insulin;    Pancreatic islet;    Alpha cell;    Beta cell;   

Others  :  1216416
DOI  :  10.1186/1471-2164-15-620

 received in 2014-03-27, accepted in 2014-07-10,  发布年份 2014

【 摘 要 】

Background

Insulin producing beta cell and glucagon producing alpha cells are colocalized in pancreatic islets in an arrangement that facilitates the coordinated release of the two principal hormones that regulate glucose homeostasis and prevent both hypoglycemia and diabetes. However, this intricate organization has also complicated the determination of the cellular source(s) of the expression of genes that are detected in the islet. This reflects a significant gap in our understanding of mouse islet physiology, which reduces the effectiveness by which mice model human islet disease.

Results

To overcome this challenge, we generated a bitransgenic reporter mouse that faithfully labels all beta and alpha cells in mouse islets to enable FACS-based purification and the generation of comprehensive transcriptomes of both populations. This facilitates systematic comparison across thousands of genes between the two major endocrine cell types of the islets of Langerhans whose principal hormones are of cardinal importance for glucose homeostasis. Our data leveraged against similar data for human beta cells reveal a core common beta cell transcriptome of 9900+ genes. Against the backdrop of overall similar beta cell transcriptomes, we describe marked differences in the repertoire of receptors and long non-coding RNAs between mouse and human beta cells.

Conclusions

The comprehensive mouse alpha and beta cell transcriptomes complemented by the comparison of the global (dis)similarities between mouse and human beta cells represent invaluable resources to boost the accuracy by which rodent models offer guidance in finding cures for human diabetes.

【 授权许可】

   
2014 Benner et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Gradwohl G, Dierich A, LeMeur M, Guillemot F: Neurogenin3 is required for the development of the four endocrine cell lineages of the pancreas. Proc Natl Acad Sci U S A 2000, 97(4):1607-1611.
• [2]Arda HE, Benitez CM, Kim SK: Gene regulatory networks governing pancreas development. Dev Cell 2013, 25(1):5-13.
• [3]Bramswig NC, Kaestner KH: Transcriptional regulation of alpha-cell differentiation. Diabetes Obes Metab 2011, 13(Suppl 1):13-20.
• [4]Schaffer AE, Taylor BL, Benthuysen JR, Liu J, Thorel F, Yuan W, Jiao Y, Kaestner KH, Herrera PL, Magnuson MA, May CL, Sander M: Nkx6.1 controls a gene regulatory network required for establishing and maintaining pancreatic Beta cell identity. PLoS Genet 2013, 9(1):e1003274.
• [5]Ben-Othman N, Courtney M, Vieira A, Pfeifer A, Druelle N, Gjernes E, Faurite B, Avolio F, Collombat P: From pancreatic islet formation to beta-cell regeneration. Diabetes Res Clin Pract 2013, 101(1):1-9.
• [6]Lin HV, Accili D: Hormonal regulation of hepatic glucose production in health and disease. Cell Metab 2011, 14(1):9-19.
• [7]Leto D, Saltiel AR: Regulation of glucose transport by insulin: traffic control of GLUT4. Nat Rev Mol Cell Biol 2012, 13(6):383-396.
• [8]Schwartz MW, Seeley RJ, Tschop MH, Woods SC, Morton GJ, Myers MG, D'Alessio D: Cooperation between brain and islet in glucose homeostasis and diabetes. Nature 2013, 503(7474):59-66.
• [9]Ramnanan CJ, Edgerton DS, Kraft G, Cherrington AD: Physiologic action of glucagon on liver glucose metabolism. Diabetes Obes Metab 2011, 13(Suppl 1):118-125.
• [10]Unger RH, Cherrington AD: Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover. J Clin Invest 2012, 122(1):4-12.
• [11]Hara M, Wang X, Kawamura T, Bindokas VP, Dizon RF, Alcoser SY, Magnuson MA, Bell GI: Transgenic mice with green fluorescent protein-labeled pancreatic beta -cells. Am J Physiol Endocrinol Metab 2003, 284(1):E177-E183.
• [12]Huising MO, van der Meulen T, Vaughan JM, Matsumoto M, Donaldson CJ, Park H, Billestrup N, Vale WW: CRFR1 is expressed on pancreatic beta cells, promotes beta cell proliferation, and potentiates insulin secretion in a glucose-dependent manner. Proc Natl Acad Sci U S A 2010, 107(2):912-917.
• [13]Zuo Y, Lubischer JL, Kang H, Tian L, Mikesh M, Marks A, Scofield VL, Maika S, Newman C, Krieg P, Thompson WJ: Fluorescent proteins expressed in mouse transgenic lines mark subsets of glia, neurons, macrophages, and dendritic cells for vital examination. J Neurosci 2004, 24(49):10999-11009.
• [14]Mortazavi A, Williams BA, McCue K, Schaeffer L, Wold B: Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat Methods 2008, 5(7):621-628.
• [15]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, et al.: Human beta cell transcriptome analysis uncovers lncRNAs that are tissue-specific, dynamically regulated, and abnormally expressed in type 2 diabetes. Cell Metab 2012, 16(4):435-448.
• [16]Nica AC, Ongen H, Irminger JC, Bosco D, Berney T, Antonarakis SE, Halban PA, Dermitzakis ET: Cell-type, allelic, and genetic signatures in the human pancreatic beta cell transcriptome. Genome Res 2013, 23(9):1554-1562.
• [17]van der Meulen T, Xie R, Kelly OG, Vale WW, Sander M, Huising MO: Urocortin 3 marks mature human primary and embryonic stem cell-derived pancreatic alpha and beta cells. PLoS One 2012, 7(12):e52181.
• [18]Li C, Chen P, Vaughan J, Blount A, Chen A, Jamieson PM, Rivier J, Smith MS, Vale W: Urocortin III is expressed in pancreatic beta-cells and stimulates insulin and glucagon secretion. Endocrinology 2003, 144(7):3216-3224.
• [19]Matsuoka TA, Artner I, Henderson E, Means A, Sander M, Stein R: The MafA transcription factor appears to be responsible for tissue-specific expression of insulin. Proc Natl Acad Sci U S A 2004, 101(9):2930-2933.
• [20]Ku GM, Kim H, Vaughn IW, Hangauer MJ, Myung Oh C, German MS, McManus MT: Research resource: RNA-Seq reveals unique features of the pancreatic beta-cell transcriptome. Mol Endocrinol 2012, 26(10):1783-1792.
• [21]da Huang W, Sherman BT, Lempicki RA: Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res 2009, 37(1):1-13.
• [22]Collombat P, Mansouri A, Hecksher-Sorensen J, Serup P, Krull J, Gradwohl G, Gruss P: Opposing actions of Arx and Pax4 in endocrine pancreas development. Genes Dev 2003, 17(20):2591-2603.
• [23]Holland AM, Gonez LJ, Naselli G, Macdonald RJ, Harrison LC: Conditional expression demonstrates the role of the homeodomain transcription factor Pdx1 in maintenance and regeneration of beta-cells in the adult pancreas. Diabetes 2005, 54(9):2586-2595.
• [24]Harrison KA, Thaler J, Pfaff SL, Gu H, Kehrl JH: Pancreas dorsal lobe agenesis and abnormal islets of Langerhans in Hlxb9-deficient mice. Nat Genet 1999, 23(1):71-75.
• [25]Guo S, Dai C, Guo M, Taylor B, Harmon JS, Sander M, Robertson RP, Powers AC, Stein R: Inactivation of specific beta cell transcription factors in type 2 diabetes. J Clin Invest 2013, 123(8):3305-3316.
• [26]Shimajiri Y, Kosaka Y, Scheel DW, Lynn FC, Kishimoto N, Wang J, Zhao S, German MS: A mouse model for monitoring islet cell genesis and developing therapies for diabetes. Dis Models Mech 2011, 4(2):268-276.
• [27]Wang S, Jensen JN, Seymour PA, Hsu W, Dor Y, Sander M, Magnuson MA, Serup P, Gu G: Sustained Neurog3 expression in hormone-expressing islet cells is required for endocrine maturation and function. Proc Natl Acad Sci U S A 2009, 106(24):9715-9720.
• [28]Dror V, Nguyen V, Walia P, Kalynyak TB, Hill JA, Johnson JD: Notch signalling suppresses apoptosis in adult human and mouse pancreatic islet cells. Diabetologia 2007, 50(12):2504-2515.
• [29]Sosa-Pineda B, Chowdhury K, Torres M, Oliver G, Gruss P: The Pax4 gene is essential for differentiation of insulin-producing beta cells in the mammalian pancreas. Nature 1997, 386(6623):399-402.
• [30]Smith SB, Ee HC, Conners JR, German MS: Paired-homeodomain transcription factor PAX4 acts as a transcriptional repressor in early pancreatic development. Mol Cell Biol 1999, 19(12):8272-8280.
• [31]Cabrera O, Berman DM, Kenyon NS, Ricordi C, Berggren PO, Caicedo A: The unique cytoarchitecture of human pancreatic islets has implications for islet cell function. Proc Natl Acad Sci U S A 2006, 103(7):2334-2339.
• [32]Brissova M, Fowler MJ, Nicholson WE, Chu A, Hirshberg B, Harlan DM, Powers AC: Assessment of human pancreatic islet architecture and composition by laser scanning confocal microscopy. J Histochem Cytochem 2005, 53(9):1087-1097.
• [33]Kim A, Miller K, Jo J, Kilimnik G, Wojcik P, Hara M: Islet architecture: A comparative study. Islets 2009, 1(2):129-136.
• [34]Rodriguez-Diaz R, Abdulreda MH, Formoso AL, Gans I, Ricordi C, Berggren PO, Caicedo A: Innervation patterns of autonomic axons in the human endocrine pancreas. Cell Metab 2011, 14(1):45-54.
• [35]Artner I, Le Lay J, Hang Y, Elghazi L, Schisler JC, Henderson E, Sosa-Pineda B, Stein R: MafB: an activator of the glucagon gene expressed in developing islet alpha- and beta-cells. Diabetes 2006, 55(2):297-304.
• [36]Riedel MJ, Asadi A, Wang R, Ao Z, Warnock GL, Kieffer TJ: Immunohistochemical characterisation of cells co-producing insulin and glucagon in the developing human pancreas. Diabetologia 2012, 55(2):372-381.
• [37]Dai C, Brissova M, Hang Y, Thompson C, Poffenberger G, Shostak A, Chen Z, Stein R, Powers AC: Islet-enriched gene expression and glucose-induced insulin secretion in human and mouse islets. Diabetologia 2012, 55(3):707-718.
• [38]Khoo C, Yang J, Weinrott SA, Kaestner KH, Naji A, Schug J, Stoffers DA: Research resource: the pdx1 cistrome of pancreatic islets. Mol Endocrinol 2012, 26(3):521-533.
• [39]Westermark P, Andersson A, Westermark GT: Islet amyloid polypeptide, islet amyloid, and diabetes mellitus. Physiol Rev 2011, 91(3):795-826.
• [40]van Belle TL, Coppieters KT, von Herrath MG: Type 1 diabetes: etiology, immunology, and therapeutic strategies. Physiol Rev 2011, 91(1):79-118.
• [41]Jayasimhan A, Mansour KP, Slattery RM: Advances in our understanding of the pathophysiology of Type 1 diabetes: lessons from the NOD mouse. Clin Sci 2014, 126(1):1-18.
• [42]Huising MO, Kruiswijk CP, Flik G: Phylogeny and evolution of class-I helical cytokines. J Endocrinol 2006, 189(1):1-25.
• [43]Kim H, Toyofuku Y, Lynn FC, Chak E, Uchida T, Mizukami H, Fujitani Y, Kawamori R, Miyatsuka T, Kosaka Y, Yang K, Honig G, van der Hart M, Kishimoto N, Wang J, Yagihashi S, Tecott LH, Watada H, German MS: Serotonin regulates pancreatic beta cell mass during pregnancy. Nat Med 2010, 16(7):804-808.
• [44]Schraenen A, Lemaire K, de Faudeur G, Hendrickx N, Granvik M, Van Lommel L, Mallet J, Vodjdani G, Gilon P, Binart N, in't Veld P, Schuit F: Placental lactogens induce serotonin biosynthesis in a subset of mouse beta cells during pregnancy. Diabetologia 2010, 53(12):2589-2599.
• [45]Hoffman BG, Robertson G, Zavaglia B, Beach M, Cullum R, Lee S, Soukhatcheva G, Li L, Wederell ED, Thiessen N, Bilenky M, Cezard T, Tam A, Kamoh B, Birol I, Dai D, Zhao Y, Hirst M, Verchere CB, Helgason CD, Marra MA, Jones SJ, Hoodless PA: Locus co-occupancy, nucleosome positioning, and H3K4me1 regulate the functionality of FOXA2-, HNF4A-, and PDX1-bound loci in islets and liver. Genome Res 2010, 20(8):1037-1051.
• [46]Bramswig NC, Everett LJ, Schug J, Dorrell C, Liu C, Luo Y, Streeter PR, Naji A, Grompe M, Kaestner KH: Epigenomic plasticity enables human pancreatic alpha to beta cell reprogramming. J Clin Invest 2013, 123(3):1275-1284.
• [47]Zhang Q, Ramracheya R, Lahmann C, Tarasov A, Bengtsson M, Braha O, Braun M, Brereton M, Collins S, Galvanovskis J, Gonzalez A, Groschner LN, Rorsman NJ, Salehi A, Travers ME, Walker JN, Gloyn AL, Gribble F, Johnson PR, Reimann F, Ashcroft FM, Rorsman P: Role of KATP channels in glucose-regulated glucagon secretion and impaired counterregulation in type 2 diabetes. Cell Metab 2013, 18(6):871-882.
• [48]Taylor BL, Liu FF, Sander M: Nkx6.1 is essential for maintaining the functional state of pancreatic beta cells. Cell reports 2013, 4(6):1262-1275.
• [49]Pasquali L, Gaulton KJ, Rodriguez-Segui SA, Mularoni L, Miguel-Escalada I, Akerman I, Tena JJ, Moran I, Gomez-Marin C, van de Bunt M, Ponsa-Cobas J, Castro N, Nammo T, Cebola I, Garcia-Hurtado J, Maestro MA, Pattou F, Piemonti L, Berney T, Gloyn AL, Ravassard P, Skarmeta JL, Muller F, McCarthy MI, Ferrer J: Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants. Nat Genet 2014, 46(2):136-143.
• [50]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 CV, Van de Casteele M, German MS, Bouwens L, Heimberg H: Transient cytokine treatment induces acinar cell reprogramming and regenerates functional beta cell mass in diabetic mice. Nat Biotechnol 2014, 32(1):76-83.
• [51]Nielsen JH, Svensson C, Galsgaard ED, Moldrup A, Billestrup N: Beta cell proliferation and growth factors. J Mol Med (Berl) 1999, 77(1):62-66.
• [52]Yamamoto T, Mita A, Ricordi C, Messinger S, Miki A, Sakuma Y, Timoneri F, Barker S, Fornoni A, Molano RD, Inverardi L, Pileggi A, Ichii H: Prolactin supplementation to culture medium improves beta-cell survival. Transplantation 2010, 89(11):1328-1335.
• [53]Parnaud G, Bosco D, Berney T, Pattou F, Kerr-Conte J, Donath MY, Bruun C, Mandrup-Poulsen T, Billestrup N, Halban PA: Proliferation of sorted human and rat beta cells. Diabetologia 2008, 51(1):91-100.
• [54]Butler AE, Cao-Minh L, Galasso R, Rizza RA, Corradin A, Cobelli C, Butler PC: Adaptive changes in pancreatic beta cell fractional area and beta cell turnover in human pregnancy. Diabetologia 2010, 53(10):2167-2176.
• [55]Fiaschi-Taesch NM, Kleinberger JW, Salim FG, Troxell R, Wills R, Tanwir M, Casinelli G, Cox AE, Takane KK, Scott DK, Stewart AF: Human pancreatic beta-cell G1/S molecule cell cycle atlas. Diabetes 2013, 62(7):2450-2459.
• [56]Maedler K, Sergeev P, Ris F, Oberholzer J, Joller-Jemelka HI, Spinas GA, Kaiser N, Halban PA, Donath MY: Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets. J Clin Invest 2002, 110(6):851-860.
• [57]Bendtzen K, Mandrup-Poulsen T, Nerup J, Nielsen JH, Dinarello CA, Svenson M: Cytotoxicity of human pI 7 interleukin-1 for pancreatic islets of Langerhans. Science 1986, 232(4757):1545-1547.
• [58]Donath MY, Storling J, Maedler K, Mandrup-Poulsen T: Inflammatory mediators and islet beta-cell failure: a link between type 1 and type 2 diabetes. J Mol Med 2003, 81(8):455-470.
• [59]Donath MY, Dalmas E, Sauter NS, Boni-Schnetzler M: Inflammation in obesity and diabetes: islet dysfunction and therapeutic opportunity. Cell Metab 2013, 17(6):860-872.
• [60]Cabili MN, Trapnell C, Goff L, Koziol M, Tazon-Vega B, Regev A, Rinn JL: Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. Genes Dev 2011, 25(18):1915-1927.
• [61]Orom UA, Shiekhattar R: Long noncoding RNAs usher in a new era in the biology of enhancers. Cell 2013, 154(6):1190-1193.
• [62]Mercer TR, Dinger ME, Mattick JS: Long non-coding RNAs: insights into functions. Nat Rev Genet 2009, 10(3):155-159.
• [63]Necsulea A, Soumillon M, Warnefors M, Liechti A, Daish T, Zeller U, Baker JC, Grutzner F, Kaessmann H: The evolution of lncRNA repertoires and expression patterns in tetrapods. Nature 2014, 505(7485):635-640.
• [64]Kutter C, Watt S, Stefflova K, Wilson MD, Goncalves A, Ponting CP, Odom DT, Marques AC: Rapid turnover of long noncoding RNAs and the evolution of gene expression. PLoS Genet 2012, 8(7):e1002841.
• [65]Couzin-Frankel J: When mice mislead. Science 2013, 342(6161):922-923. 925
• [66]Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, Batut P, Chaisson M, Gingeras TR: STAR: ultrafast universal RNA-seq aligner. Bioinformatics 2013, 29(1):15-21.
• [67]Quinlan AR, Hall IM: BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 2010, 26(6):841-842.
• [68]Anders S, Huber W: Differential expression analysis for sequence count data. Genome Biol 2010, 11(10):R106.
• [69]Tennant BR, Robertson AG, Kramer M, Li L, Zhang X, Beach M, Thiessen N, Chiu R, Mungall K, Whiting CJ, Sabatini PV, Kim A, Gottardo R, Marra MA, Lynn FC, Jones SJ, Hoodless PA, Hoffman BG: Identification and analysis of murine pancreatic islet enhancers. Diabetologia 2013, 56(3):542-552.
• [70]Heinz S, Benner C, Spann N, Bertolino E, Lin YC, Laslo P, Cheng JX, Murre C, Singh H, Glass CK: Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell 2010, 38(4):576-589.
• [71]Bailey TL, Noble WS: Searching for statistically significant regulatory modules. Bioinformatics 2003, 19(Suppl 2):ii16-ii25.
• [72]Wasserman WW, Sandelin A: Applied bioinformatics for the identification of regulatory elements. Nat Rev Genet 2004, 5(4):276-287.
• [73]Trapnell C, Williams BA, Pertea G, Mortazavi A, Kwan G, van Baren MJ, Salzberg SL, Wold BJ, Pachter L: Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat Biotechnol 2010, 28(5):511-515.