Journal of Gastroenterology

, Volume 50, Issue 1, pp 46–57 | Cite as

The human gastrointestinal tract-specific transcriptome and proteome as defined by RNA sequencing and antibody-based profiling

  • Gabriela Gremel
  • Alkwin Wanders
  • Jonathan Cedernaes
  • Linn Fagerberg
  • Björn Hallström
  • Karolina Edlund
  • Evelina Sjöstedt
  • Mathias Uhlén
  • Fredrik PonténEmail author
Original Article—Alimentary Tract



The gastrointestinal tract (GIT) is subdivided into different anatomical organs with many shared functions and characteristics, but also distinct differences. We have combined a genome-wide transcriptomics analysis with immunohistochemistry-based protein profiling to describe the gene and protein expression patterns that define the human GIT.


RNA sequencing data derived from stomach, duodenum, jejunum/ileum and colon specimens were compared to gene expression levels in 23 other normal human tissues analysed with the same method. Protein profiling based on immunohistochemistry and tissue microarrays was used to sub-localize the corresponding proteins with GIT-specific expression into sub-cellular compartments and cell types.


Approximately 75 % of all human protein-coding genes were expressed in at least one of the GIT tissues. Only 51 genes showed enriched expression in either one of the GIT tissues and an additional 83 genes were enriched in two or more GIT tissues. The list of GIT-enriched genes with validated protein expression patterns included various well-known but also previously uncharacterised or poorly studied genes. For instance, the colon-enriched expression of NXPE family member 1 (NXPE1) was established, while NLR family, pyrin domain-containing 6 (NLRP6) expression was primarily found in the human small intestine.


We have applied a genome-wide analysis based on transcriptomics and antibody-based protein profiling to identify genes that are expressed in a specific manner within the human GIT. These genes and proteins constitute important starting points for an improved understanding of the normal function and the different states of disease associated with the GIT.


RNA expression Immunohistochemistry Gastrointestinal tract 



Funding was provided by the Knut and Alice Wallenberg Foundation. Pathologists and staff at the Department of Clinical Pathology, Uppsala University Hospital are greatly acknowledged for providing the tissues used in the study, in particular, the authors would like to thank Simin Tahmasebpoor for excellent help with preparing frozen tissues for RNA extraction. The authors also wish to thank the staff of the Human Protein Atlas project in both Sweden and India for their efforts in generating the Human Protein Atlas.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical statement

The study was approved by the Uppsala Ethical Review Board (Reference 2011/473).

Supplementary material

535_2014_958_MOESM1_ESM.doc (40 kb)
Supplementary material 1 (DOC 40 kb)
535_2014_958_MOESM2_ESM.doc (136 kb)
Supplementary material 2 (DOC 136 kb)
535_2014_958_MOESM3_ESM.docx (469 kb)
Supplementary material 3 (DOCX 468 kb)
535_2014_958_MOESM4_ESM.doc (42 kb)
Supplementary material 4 (DOC 41 kb)


  1. 1.
    Mayer EA. Gut feelings: the emerging biology of gut-brain communication. Nat Rev Neurosci. 2011;12:453–66.PubMedCrossRefGoogle Scholar
  2. 2.
    Holzer P, Reichmann F, Farzi A. Neuropeptide Y, peptide YY and pancreatic polypeptide in the gut-brain axis. Neuropeptides. 2012;46:261–74.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Neish AS. Microbes in gastrointestinal health and disease. Gastroenterology. 2009;136:65–80.PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    O’Hara AM, Shanahan F. The gut flora as a forgotten organ. EMBO Rep. 2006;7:688–93.PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Round JL, Mazmanian SK. The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol. 2009;9:313–23.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Molodecky NA, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology. 2012;142:46–54 (e42 quiz e30).PubMedCrossRefGoogle Scholar
  7. 7.
    Ferlay J, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–917.PubMedCrossRefGoogle Scholar
  8. 8.
    Dalerba P, et al. Single-cell dissection of transcriptional heterogeneity in human colon tumors. Nat Biotechnol. 2011;29:1120–7.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Comelli EM, et al. Biomarkers of human gastrointestinal tract regions. Mamm Genome. 2009;20:516–27.PubMedCrossRefGoogle Scholar
  10. 10.
    Fagerberg L, et al. Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol Cell Proteomics. 2014;13(2):397–406.PubMedCrossRefGoogle Scholar
  11. 11.
    Ponten F, et al. The Human Protein Atlas as a proteomic resource for biomarker discovery. J Intern Med. 2011;270:428–46.PubMedCrossRefGoogle Scholar
  12. 12.
    Kircher M, Sawyer S, Meyer M. Double indexing overcomes inaccuracies in multiplex sequencing on the Illumina platform. Nucleic Acids Res. 2012;40:e3.PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Ponten F, Jirstrom K, Uhlen M. The Human Protein Atlas–a tool for pathology. J Pathol. 2008;216:387–93.PubMedCrossRefGoogle Scholar
  14. 14.
    Kampf C, et al. Antibody-based tissue profiling as a tool in clinical proteomics. Clin Proteomics. 2004;1:285–300.CrossRefGoogle Scholar
  15. 15.
    Trapnell C, et al. Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat Biotechnol. 2010;28:511–5.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Hebenstreit D, et al. RNA sequencing reveals two major classes of gene expression levels in metazoan cells. Mol Syst Biol. 2011;7:497.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Kageyama T. Pepsinogens, progastricsins, and prochymosins: structure, function, evolution, and development. Cell Mol Life Sci. 2002;59:288–306.PubMedCrossRefGoogle Scholar
  18. 18.
    van Driel IR, Callaghan JM. Proton and potassium transport by H+/K(+)-ATPases. Clin Exp Pharmacol Physiol. 1995;22:952–60.PubMedCrossRefGoogle Scholar
  19. 19.
    Alpers DH, Russell-Jones G. Gastric intrinsic factor: the gastric and small intestinal stages of cobalamin absorption. a personal journey. Biochimie. 2013;95:989–94.PubMedCrossRefGoogle Scholar
  20. 20.
    Ma K, Mallidis C, Bhasin S. The role of Y chromosome deletions in male infertility. Euro J Endocrinol. 2000;142:418–30.CrossRefGoogle Scholar
  21. 21.
    Uhlen M, et al. Towards a knowledge-based Human Protein Atlas. Nat Biotechnol. 2010;28:1248–50.PubMedCrossRefGoogle Scholar
  22. 22.
    Fujimoto K, Polonsky KS. Pdx1 and other factors that regulate pancreatic beta-cell survival. Diabetes Obes Metab. 2009;11(Suppl 4):30–7.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Guz Y, et al. Expression of murine STF-1, a putative insulin gene transcription factor, in beta cells of pancreas, duodenal epithelium and pancreatic exocrine and endocrine progenitors during ontogeny. Development. 1995;121:11–8.PubMedGoogle Scholar
  24. 24.
    Chen C, Sibley E. Expression profiling identifies novel gene targets and functions for Pdx1 in the duodenum of mature mice. Am J Physiol Gastrointest Liver Physiol. 2012;302:G407–19.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Holland AM, et al. The Parahox gene Pdx1 is required to maintain positional identity in the adult foregut. Int J Dev Biol. 2013;57:391–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Ose R, et al. PCDH24-induced contact inhibition involves downregulation of beta-catenin signaling. Mol Oncol. 2009;3:54–66.PubMedCrossRefGoogle Scholar
  27. 27.
    Okazaki N, et al. Protocadherin LKC, a new candidate for a tumor suppressor of colon and liver cancers, its association with contact inhibition of cell proliferation. Carcinogenesis. 2002;23:1139–48.PubMedCrossRefGoogle Scholar
  28. 28.
    Mashima H, et al. INSL5 may be a unique marker of colorectal endocrine cells and neuroendocrine tumors. Biochem Biophys Res Commun. 2013;432:586–92.PubMedCrossRefGoogle Scholar
  29. 29.
    Thanasupawat T, et al. INSL5 is a novel marker for human enteroendocrine cells of the large intestine and neuroendocrine tumours. Oncol Rep. 2013;29:149–54.PubMedGoogle Scholar
  30. 30.
    Conklin D, et al. Identification of INSL5, a new member of the insulin superfamily. Genomics. 1999;60:50–6.PubMedCrossRefGoogle Scholar
  31. 31.
    Liu C, et al. INSL5 is a high affinity specific agonist for GPCR142 (GPR100). J Biol Chem. 2005;280:292–300.PubMedCrossRefGoogle Scholar
  32. 32.
    Pemberton AD, et al. Innate BALB/c enteric epithelial responses to Trichinella spiralis: inducible expression of a novel goblet cell lectin, intelectin-2, and its natural deletion in C57BL/10 mice. J Immunology. 2004;173:1894–901.CrossRefGoogle Scholar
  33. 33.
    Wrackmeyer U, et al. Intelectin: a novel lipid raft-associated protein in the enterocyte brush border. Biochemistry. 2006;45:9188–97.PubMedCrossRefGoogle Scholar
  34. 34.
    Elinav E, et al. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell. 2011;145:745–57.PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Hu B, et al. Microbiota-induced activation of epithelial IL-6 signaling links inflammasome-driven inflammation with transmissible cancer. Proc Natl Acad Sci. 2013;110:9862–7.PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Sun Y, et al. Stress-induced corticotropin-releasing hormone-mediated NLRP6 inflammasome inhibition and transmissible enteritis in mice. Gastroenterology. 2013;144(1478–87):e8.Google Scholar
  37. 37.
    Agius L. Glucokinase and molecular aspects of liver glycogen metabolism. Biochem J. 2008;414:1–18.PubMedCrossRefGoogle Scholar
  38. 38.
    Gosmain Y, et al. Glucagon gene expression in the endocrine pancreas: the role of the transcription factor Pax6 in alpha-cell differentiation, glucagon biosynthesis and secretion. Diabetes Obes Metab. 2011;13(Suppl 1):31–8.PubMedCrossRefGoogle Scholar
  39. 39.
    Bu H, et al. Anterior gradient 2 and 3–two prototype androgen-responsive genes transcriptionally upregulated by androgens and by oestrogens in prostate cancer cells. FEBS J. 2013;280:1249–66.PubMedCrossRefGoogle Scholar
  40. 40.
    Diggle CP, et al. Ketohexokinase: expression and localization of the principal fructose-metabolizing enzyme. J Histochem Cytochem. 2009;57:763–74.PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Shi H, et al. Overexpression of aminoacylase 1 is associated with colorectal cancer progression. Hum Pathol. 2013;44:1089–97.PubMedCrossRefGoogle Scholar
  42. 42.
    Hsiao LL, et al. A compendium of gene expression in normal human tissues. Physiol Genomics. 2001;7:97–104.PubMedGoogle Scholar
  43. 43.
    Shyamsundar R, et al. A DNA microarray survey of gene expression in normal human tissues. Genome Biol. 2005;6:R22.PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Lukk M, et al. A global map of human gene expression. Nat Biotechnol. 2010;28:322–4.PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Hwang PI, et al. Tissue-specific gene expression templates for accurate molecular characterization of the normal physiological states of multiple human tissues with implication in development and cancer studies. BMC Genomics. 2011;12:439.PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Magnusson K, et al. SATB2 in combination with cytokeratin 20 identifies over 95% of all colorectal carcinomas. Am J Surg Pathol. 2011;35:937–48.PubMedCrossRefGoogle Scholar
  47. 47.
    Eberhard J, et al. A cohort study of the prognostic and treatment predictive value of SATB2 expression in colorectal cancer. Br J Cancer. 2012;106:931–8.PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Ehlen A, et al. Expression of the RNA-binding protein RBM3 is associated with a favourable prognosis and cisplatin sensitivity in epithelial ovarian cancer. J Transl Med. 2010;8:78.PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Jonsson L, et al. Low RBM3 protein expression correlates with tumour progression and poor prognosis in malignant melanoma: an analysis of 215 cases from the Malmo Diet and Cancer Study. J Transl Med. 2011;9:114.PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    Boman K, et al. Decreased expression of RBM3 correlates with tumour progression and poor prognosis in urinary bladder cancer. Histopathology. 2012;61:147.CrossRefGoogle Scholar
  51. 51.
    Pacha J, Sumova A. Circadian regulation of epithelial functions in the intestine. Acta Physiol (Oxf). 2013;208:11–24.CrossRefGoogle Scholar

Copyright information

© Springer Japan 2014

Authors and Affiliations

  • Gabriela Gremel
    • 1
    • 2
  • Alkwin Wanders
    • 1
  • Jonathan Cedernaes
    • 3
  • Linn Fagerberg
    • 4
  • Björn Hallström
    • 4
  • Karolina Edlund
    • 1
    • 2
  • Evelina Sjöstedt
    • 1
    • 2
  • Mathias Uhlén
    • 4
  • Fredrik Pontén
    • 1
    • 2
    Email author
  1. 1.Department of Immunology, Genetics and Pathology, Rudbeck LaboratoryUppsala UniversityUppsalaSweden
  2. 2.Science for Life LaboratoryUppsala UniversityUppsalaSweden
  3. 3.Department of NeuroscienceUppsala UniversityUppsalaSweden
  4. 4.Science for Life LaboratoryRoyal Institute of TechnologyStockholmSweden

Personalised recommendations