Thymus Gene Coexpression Networks: A Comparative Study in Children with and Without Down Syndrome

  • Carlos Alberto Moreira-FilhoEmail author
  • Silvia Yumi Bando
  • Fernanda Bernardi Bertonha
  • Filipi Nascimento Silva
  • Luciano da Fontoura Costa
  • Magda Carneiro-Sampaio


In this chapter we characterized trisomy 21-driven transcriptional alterations in human thymus through gene coexpression network (GCN) analysis. We used whole thymic tissue (corticomedullar sections)—obtained at heart surgery from Down syndrome (DS) and karyotipically normal individuals (CT)—and a network-based approach for GCN analysis allowing the study of interactions between all the system’s constituents based on community detection. Changes in the degree of connections observed for hierarchically important hubs in DS and CT gene networks corresponded to sub-network changes, i.e. module (communities) changes. Distinct communities of highly interconnected gene sets were topologically identified for DS and CT networks. Trisomy 21 gene dysregulation in thymus may therefore be viewed as the breakdown and altered reorganization of functional modules.


Down Syndrome Differentially Express Community Detection Duchenne Muscular Dystrophy Patient Thymic Epithelial Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Abramson J, Giraud M, Benoist C et al (2010) Aire’s partners in the molecular control of immunological tolerance. Cell 140:123–135PubMedCrossRefGoogle Scholar
  2. Aït Yahya-Graison E, Aubert J, Dauphinot L et al (2007) Classification of human chromosome 21 gene-expression variations in Down syndrome: impact on disease phenotypes. Am J Hum Genet 81:475–91PubMedCentralPubMedCrossRefGoogle Scholar
  3. Anderson G, Takahama Y (2012) Thymic epithelial cells: working class heroes for T cell development and repertoire selection. Trends Immunol 33:256–263PubMedCrossRefGoogle Scholar
  4. Awad S, Al-Dosari MS, Al-Yacoub N et al (2013) Mutation in PHC1 implicates chromatin remodeling in primary microcephaly pathogenesis. Hum Mol Genet 22:2200–2213PubMedCrossRefGoogle Scholar
  5. Banchereau R, Jordan-Villegas A, Ardura M et al (2012) Host immune transcriptional profiles reflect the variability in clinical disease manifestations in patients with Staphylococcus aureus infections. PLoS ONE 7(4):e34390PubMedCentralPubMedCrossRefGoogle Scholar
  6. Bando SY, Silva FN, Costa Lda F et al (2013) Complex network analysis of CA3 transcriptome reveals pathogenic and compensatory pathways in refractory temporal lobe epilepsy. PLoS ONE 8:e79913PubMedCentralPubMedCrossRefGoogle Scholar
  7. Barabási AL, Oltvai ZN (2004) Network biology: understanding the cell’s functional organization. Nat Rev Genet 5:101–113PubMedCrossRefGoogle Scholar
  8. Barabási AL, Gulbahce N, Loscalzo J (2011) Network medicine: a network based approach to human disease. Nat Rev Genet 13:56–68CrossRefGoogle Scholar
  9. Barnard A, Layton D, Hince M et al (2008) Impact of the neuroendocrine system on thymus and bone marrow function. Neuroimmunomodulation 15:7–18PubMedCrossRefGoogle Scholar
  10. Berthelot JM, le Goff B, Maugars Y (2010) Thymic Hassall’s corpuscles, regulatory T-cells, and rheumatoid arthritis. Semin Arthritis Rheum 39:347–355PubMedCrossRefGoogle Scholar
  11. Bloemers BL, Bont L, de Weger RA et al (2011) Decreased thymic output accounts for decreased naive T cell numbers in children with Down syndrome. J Immunol 186:4500–4507PubMedCrossRefGoogle Scholar
  12. Blondel VD, Guillaume JL, Lambiotte R et al (2008) Fast unfolding of communities in large networks. J Stat Mech. doi:10.1088/1742-5468/2008/10/P10008Google Scholar
  13. Boada-Romero E, Letek M, Fleischer A et al (2013) TMEM59 defines a novel ATG16L1-binding motif that promotes local activation of LC3. EMBO J 32:566–582PubMedCentralPubMedCrossRefGoogle Scholar
  14. Chaussabel D, Baldwin N (2014) Democratizing systems immunology with modular transcriptional repertoire analyses. Nat Rev Immunol 14:271–280PubMedCentralPubMedCrossRefGoogle Scholar
  15. Chen H, Xu C, Jin Q et al (2014) S100 protein family in human cancer. Am J Cancer Res 4:89–115PubMedCentralPubMedGoogle Scholar
  16. Clauset A, Newman MEJ, Moore C (2004) Finding community structure in very large networks. Phys Rev E 70:066111CrossRefGoogle Scholar
  17. De Leon-Luis J, Santolaya J, Gamez F et al (2011) Sonographic thymic measurements in Down syndrome fetuses. Prenat Diagn 31:841–845PubMedGoogle Scholar
  18. Drumea-Mirancea M, Wessels JT, Müller CA et al (2006) Characterization of a conduit system containing laminin-5 in the human thymus: a potential transport system for small molecules. J Cell Sci 119:1396–1405PubMedCrossRefGoogle Scholar
  19. Estève PO, Terragni J, Deepti K et al (2014) Methyllysine reader plant homeodomain (PHD) finger protein 20-like 1 (PHF20L1) antagonizes DNA (Cytosine-5) methyltransferase 1 (DNMT1) proteasomal degradation. J Biol Chem 289:8277–8287PubMedCentralPubMedCrossRefGoogle Scholar
  20. Gallo EM, Winslow MM, Canté-Barrett K et al (2007) Calcineurin sets the bandwidth for discrimination of signals during thymocyte development. Nature 450:731–735PubMedCrossRefGoogle Scholar
  21. Gérard A, Ghiotto M, Fos C et al (2009) Dok-4 is a novel negative regulator of T cell activation. J Immunol 182:7681–7689PubMedCentralPubMedCrossRefGoogle Scholar
  22. Guillemot L, Spadaro D, Citi S (2013) The junctional proteins cingulin and paracingulin modulate the expression of tight junction protein genes through GATA-4. PLoS ONE 8:e55873PubMedCentralPubMedCrossRefGoogle Scholar
  23. Guittard G, Gérard A, Dupuis-Coronas S et al (2009) Cutting edge: Dok-1 and Dok-2 adaptor molecules are regulated by phosphatidylinositol 5-phosphate production in T cells. J Immunol 182:3974–3978PubMedCrossRefGoogle Scholar
  24. Hamazaki Y, Fujita H, Kobayashi T et al (2007) Medullary thymic epithelial cells expressing Aire represent a unique lineagederived from cells expressing claudin. Nat Immunol 8:304–311PubMedCrossRefGoogle Scholar
  25. Hirao K, Natsuka Y, Tamura T et al (2006) EDEM3, a soluble EDEM homolog, enhances glycoprotein endoplasmic reticulum-associated degradation and mannosetrimming. J Biol Chem 281:9650–9658PubMedCrossRefGoogle Scholar
  26. Holländer GA (2007) Claudins provide a breath of fresh Aire. Nat Immunol 8:234–236. PubMed PMID: 17304232PubMedCrossRefGoogle Scholar
  27. Ishihara M, Araya N, Sato T et al (2013) Preapoptotic protease calpain-2 is frequently suppressed in adult T-cell leukemia. Blood 121:4340–4347PubMedCentralPubMedCrossRefGoogle Scholar
  28. Izsepi E, Himer L, Szilagyi O et al (2013) Membrane microdomain organization, calcium signal, and NFAT activation as an important axis in polarized Th cell function. Cytometry A 83:185–196PubMedCrossRefGoogle Scholar
  29. Jablonska-Mestanova V, Sisovsky V, Danisovic L et al (2013) The normal human newborns thymus. Bratisl Lek Listy 114:402–408PubMedGoogle Scholar
  30. Kammerer R, Stober D, Singer BB et al (2001) Carcinoembryonic antigen-related cell adhesion molecule 1 on murine dendritic cells is a potent regulator of T cell stimulation. J Immunol 166:6537–6544PubMedCrossRefGoogle Scholar
  31. Kanzaki S, Yamaguchi A, Yamaguchi K et al (2010) Thymic alterations in GM2 Gangliosidoses model mice. PLoS ONE 5(8):e12105PubMedCentralPubMedCrossRefGoogle Scholar
  32. Karl K, Heling KS, Sarut Lopez A et al (2012) Thymic-thoracic ratio in fetuses with trisomy 21, 18 or 13. Ultrasound Obstet Gynecol 40:412–417PubMedCrossRefGoogle Scholar
  33. Kim W, Bennett EJ, Huttlin EL et al (2011) Systematic and quantitative assessment of the ubiquitin-modified proteome. Mol Cell 44:325–340PubMedCentralPubMedCrossRefGoogle Scholar
  34. Kim S, Hill A, Warman ML et al (2012) Golgi disruption and early embryonic lethality in mice lacking USO1. PLoS ONE 7(11):e50530PubMedCentralPubMedCrossRefGoogle Scholar
  35. Korbel JO, Tirosh-Wagner T, Urban AE et al (2009) The genetic architecture of Down syndrome phenotypes revealed by high-resolution analysis of human segmental trisomies. Proc Natl Acad Sci U S A 106:12031–12036PubMedCentralPubMedCrossRefGoogle Scholar
  36. Krishnan N, Thellin O, Buckley DJ et al (2003) Prolactin suppresses glucocorticoid-induced thymocyte apoptosis in vivo. Endocrinology 144:2102–2110PubMedCrossRefGoogle Scholar
  37. Kusters MA, Gemen EF, Verstegen RH et al (2010) Both normal memory counts and decreased naive cells favor intrinsic defect over early senescence of Down syndrome T lymphocytes. Pediatr Res 67:557–562PubMedCrossRefGoogle Scholar
  38. Larocca LM, Lauriola L, Ranelletti FO et al (1990) Morphological and immunohistochemical study of Down syndrome thymus. J Med Genet Suppl. 7:225–230PubMedGoogle Scholar
  39. Levin SM, Schlesinger Z, Handzel T et al (1979) Thymic deficiency in Down’s syndrome. Pediatrics 63:80–87PubMedGoogle Scholar
  40. Liang H, Coles AH, Zhu Z et al (2007) Noncanonical Wnt signaling promotes apoptosis in thymocyte development. J Exp Med 204:3077–3084PubMedCentralPubMedCrossRefGoogle Scholar
  41. Lima FA, Moreira-Filho CA, Ramos PL et al (2011) Decreased AIRE expression and global thymic hypofunction in Down syndrome. J Immunol 187:3422–3430PubMedCrossRefGoogle Scholar
  42. Lorenzo LP, Shatynski KE, Clark S et al (2013) Defective thymic progenitor development and mature T-cell responses in a mouse model for Down syndrome. Immunology 139:447–458PubMedCentralPubMedCrossRefGoogle Scholar
  43. Low SH, Vasanji A, Nanduri J et al (2006) Syntaxins 3 and 4 are concentrated in separate clusters on the plasma membranebefore the establishment of cell polarity. Mol Biol Cell 17:977–989PubMedCentralPubMedCrossRefGoogle Scholar
  44. Macedo C, Evangelista AF, Magalhães DA et al (2009) Evidence for a network transcriptional control of promiscuous gene expression in medullary thymic epithelial cells. Mol Immunol 46:3240–3244PubMedCrossRefGoogle Scholar
  45. Markus MA, Morris BJ (2009) RBM4: a multifunctional RNA-binding protein. Int J Biochem Cell Biol 41:740–743PubMedCrossRefGoogle Scholar
  46. Mathis D, Benoist C (2009) Aire. Annu Rev Immunol 27:287–312PubMedCrossRefGoogle Scholar
  47. Mégarbané A, Ravel A, Mircher C et al (2009) The 50th anniversary of the discovery of trisomy 21: the past, present, and future of research and treatment of Down syndrome. Genet Med 11:611–616PubMedCrossRefGoogle Scholar
  48. Mingueneau M, Kreslavsky T, Gray D et al (2013) The transcriptional landscape of αβ T cell differentiation. Nat Immunol 14:619–632PubMedCrossRefGoogle Scholar
  49. Morgan D, Goodship J, Essner JJ et al (2002) The left-right determinant inversin has highly conserved ankyrin repeat and IQ domains and interacts with calmodulin. Hum Genet 110:377–384PubMedCrossRefGoogle Scholar
  50. Mou F, Praskova M, Xia F et al (2012) The Mst1 and Mst2 kinases control activation of rho family GTPases and thymic egress of mature thymocytes. J Exp Med 209:741–759PubMedCentralPubMedCrossRefGoogle Scholar
  51. Nakayama F, Umeda S, Ichimiya T et al (2013) Sulfation of keratan sulfate proteoglycan reduces radiation-induced apoptosis in human Burkitt’s lymphoma cell lines. FEBS Lett 587:231–237PubMedCrossRefGoogle Scholar
  52. Narayanan T, Subramaniam S (2013) Community structure analysis of gene interaction networks in Duchenne Muscular Dystrophy. PLoS ONE 8(6):e67237PubMedCentralPubMedCrossRefGoogle Scholar
  53. Newman MEJ, Girvan M (2004) Finding and evaluating community structure in networks. Phys Rev E 69:026113CrossRefGoogle Scholar
  54. Obermoser G, Presnell S, Domico K et al (2013) Systems scale interactive exploration reveals quantitative and qualitative differences in response to influenza and pneumococcal vaccines. Immunity 38:831–844PubMedCentralPubMedCrossRefGoogle Scholar
  55. Oh J, Wu N, Baravalle G et al (2013) MARCH1-mediated MHCII ubiquitination promotes dendritic cell selection of natural regulatory T cells. J Exp Med 210:1069–1077PubMedCentralPubMedCrossRefGoogle Scholar
  56. Pellegrini FP, Marinoni M, Frangione V et al (2012) Down syndrome, autoimmunity and T regulatory cells. Clin Exp Immunol 169:238–243PubMedCentralPubMedCrossRefGoogle Scholar
  57. Pereira PL, Magnol L, Sahún I et al (2009) A new mouse model for the trisomy of the Abcg1-U2af1 region reveals the complexity of the combinatorial genetic code of Down syndrome. Hum Mol Genet 18:4756–6926PubMedCentralPubMedCrossRefGoogle Scholar
  58. Prandini P, Deutsch S, Lyle R et al (2007) Natural gene-expression variation in Down syndrome modulates the outcome of gene-dosage imbalance. Am J Hum Genet 81:252–263PubMedCentralPubMedCrossRefGoogle Scholar
  59. Puleston DJ, Simon AK (2014) Autophagy in the immune system. Immunology 141:1–8PubMedCentralPubMedCrossRefGoogle Scholar
  60. Ruiz JC, Bruick RK (2014) F-box and leucine-rich repeat protein 5 (FBXL5): sensing intracellular iron and oxygen. J Inorg Biochem 133:73–77PubMedCrossRefGoogle Scholar
  61. Sahni N, Yi S, Zhong Q et al (2013) Edgotype: a fundamental link between genotype and phenotype. Curr Opin Genet Dev 23:649–657PubMedCentralPubMedCrossRefGoogle Scholar
  62. Sakurai C, Hashimoto H, Nakanishi H et al (2012) SNAP-23 regulates phagosome formation and maturation in macrophages. Mol Biol Cell 23:4849–4863PubMedCentralPubMedCrossRefGoogle Scholar
  63. Sasada T, Ghendler Y, Neveu JM et al (2001) A naturally processed mitochondrial self-peptide in complex with thymic MHC molecules functions as a selecting ligand for a viral-specific T cell receptor. J Exp Med 194:883–892PubMedCentralPubMedCrossRefGoogle Scholar
  64. Spitz F, Gonzalez F, Duboule D (2003) A global control region defines a chromosomal regulatory landscape containing the HoxD cluster. Cell 113:405–417PubMedCrossRefGoogle Scholar
  65. Stoika R, Melmed S (2002) Expression and function of pituitary tumour transforming gene for T-lymphocyte activation. Br J Haematol 119:1070–1074PubMedCrossRefGoogle Scholar
  66. Takahashi K, Yoshida N, Murakami N et al (2007) Dynamic regulation of p53 subnuclearlocalization and senescence by MORC3. Mol Biol Cell 18:1701–1709PubMedCentralPubMedCrossRefGoogle Scholar
  67. Tanimoto K, Suzuki K, Jokitalo E et al (2011) Characterization of YIPF3 and YIPF4, cis-Golgi Localizing Yip domain family proteins. Cell Struct Funct 36:171–185PubMedCrossRefGoogle Scholar
  68. Tian Y, Chang JC, Fan EY et al (2013) Adaptor complexAP2/PICALM, through interaction with LC3, targets Alzheimer’s APP-CTF forterminal degradation via autophagy. Proc Natl Acad Sci U S A 110:17071–17076PubMedCentralPubMedCrossRefGoogle Scholar
  69. Veland IR, Montjean R, Eley L et al (2013) Inversin/Nephrocystin-2 is required for fibroblast polarity and directional cell migration. PLoS ONE 8:e60193PubMedCentralPubMedCrossRefGoogle Scholar
  70. Xu Y, Li W, Liu X et al (2013) Identification of dysregulated microRNAs in lymphocytes from children with Down syndrome. Gene 530:278–286PubMedCrossRefGoogle Scholar
  71. Yang H, Youm YH, Vandanmagsar B et al (2009) Obesity accelerates thymic aging. Blood 114:3803–3812PubMedCentralPubMedCrossRefGoogle Scholar
  72. Young DJ, Stoddart A, Nakitandwe J et al (2014) Knockdown of Hnrnpa0, a del(5q) gene, alters myeloid cell fate in murine cells through regulation of AU-rich transcripts. Haematologica 99(6):1032–1040 PubMed PMID: 24532040PubMedCentralPubMedCrossRefGoogle Scholar
  73. Zhou D, Medoff BD, Chen L et al (2008) The Nore1B/Mst1 complex restrains antigen receptor-induced proliferation of naïve T cells. Proc Natl Acad Sci U S A 105:20321–20326PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • Carlos Alberto Moreira-Filho
    • 1
    Email author
  • Silvia Yumi Bando
    • 2
  • Fernanda Bernardi Bertonha
    • 2
  • Filipi Nascimento Silva
    • 3
  • Luciano da Fontoura Costa
    • 3
  • Magda Carneiro-Sampaio
    • 2
  1. 1.Departamento de PediatriaFaculdade de Medicina da Universidade de São PauloSão PauloBrazil
  2. 2.Departamento de PediatriaFaculdade de Medicina da Universidade de São PauloSão PauloBrazil
  3. 3.Instituto de Física de São CarlosUniversidade de São PauloSão CarlosBrazil

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