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Epigenetic control of the immune system: a lesson from Kabuki syndrome

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Abstract

Kabuki syndrome (KS) is a rare multi-systemic disorder characterized by a distinct face, postnatal growth deficiency, mild-to-moderate intellectual disability, skeletal and visceral (mainly cardiovascular, renal, and skeletal) malformations, dermatoglyphic abnormalities. Its cause is related to mutations of two genes: KMT2D (histone-lysine N-methyltransferase 2D) and KDM6A (lysine-specific demethylase 6A), both functioning as epigenetic modulators through histone modifications in the course of embryogenesis and in several biological processes. Epigenetic regulation is defined as the complex of hereditable modifications to DNA and histone proteins that modulates gene expression in the absence of DNA nucleotide sequence changes. Different human disorders are caused by mutations of genes involved in the epigenetic regulation, and not surprisingly, all these share developmental defects, disturbed growth (in excess or defect), multiple congenital organ malformations, and also hematological and immunological defects. In particular, most KS patients show increased susceptibility to infections and have reduced serum immunoglobulin levels, while some suffer also from autoimmune manifestations, such as idiopathic thrombocytopenic purpura, hemolytic anemia, autoimmune thyroiditis, and vitiligo. Herein we review the immunological aspects of KS and propose a novel model to account for the immune dysfunction observed in this condition.

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References

  1. Niikawa N, Matsuura N, Fukushima Y, Ohsawa T, Kajii T. Kabuki make-up syndrome: a syndrome of mental retardation, unusual facies, large and protruding ears, and postnatal growth deficiency. J Pediatr. 1981;99:565–9.

    Article  CAS  PubMed  Google Scholar 

  2. Kuroki Y, Suzuki Y, Chyo H, Hata A, Matsui I. A new malformation syndrome of long palpebral fissures, large ears, depressed nasal tip, and skeletal anomalies associated with postnatal dwarfism and mental retardation. J Pediatr. 1981;99:570–3.

    Article  CAS  PubMed  Google Scholar 

  3. Niikawa N, Kuroki Y, Kajii T, Matsuura N, lshikiriyarna S, Tonoki H, et al. Kabuki make-up (Niikawa-Kuroki) syndrome: a study of 62 patients. Am J Med Genet. 1988;31:562–9.

    Article  Google Scholar 

  4. Hannibal MC, Buckingham KJ, Ng SB, Ming JE, Beck AE, McMillin MJ, et al. Spectrum of MLL2 (ALR) mutations in 110 cases of Kabuki syndrome. Am J Med Genet A. 2011;155A:1511–6.

    Article  PubMed  Google Scholar 

  5. Ng SB, Bigham AW, Buckingham KJ, Hannibal MC, McMillin MJ, Gildersleeve HI, et al. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat Genet. 2010;42:790–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Paulussen AD, Stegmann AP, Blok MJ, Tserpelis D, Posma-Velter C, Detisch Y, et al. MLL2 mutation spectrum in 45 patients with Kabuki syndrome. Hum Mutat. 2011;32:E2018–25.

    Article  CAS  PubMed  Google Scholar 

  7. Lederer D, Grisart B, Digilio MC, Benoit V, Crespin M, Ghariani SC, et al. Deletion of KDM6A, a histone demethylase interacting with MLL2, in three patients with Kabuki syndrome. Am J Hum Genet. 2012;90:119–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Miyake N, Koshimizu E, Okamoto N, Mizuno S, Ogata T, Nagai T, et al. MLL2 and KDM6A mutations in patients with Kabuki syndrome. Am J Med Genet A. 2013;161A:2234–43.

    Article  PubMed  Google Scholar 

  9. Hoffman JD, Ciprero KL, Sullivan KE, Kaplan PB, McDonald-McGinn DM, Zackai EH, et al. Immune abnormalities are a frequent manifestation of Kabuki syndrome. Am J Med Genet A. 2005;135:278–81.

    Article  PubMed  Google Scholar 

  10. Lin JL, Lee WI, Huang JL, Chen PK, Chan KC, Lo LJ, et al. Immunologic assessment and KMT2D mutation detection in Kabuki syndrome. Clin Genet. 2014. doi:10.1111/cge.12484.

    Google Scholar 

  11. Ming JE, Russell KL, McDonald-McGinn DM, Zackai EH. Autoimmune disorders in Kabuki syndrome. Am J Med Genet A. 2005;132A:260–2.

    Article  PubMed  Google Scholar 

  12. Morin RD, Johnson NA, Severson TM, Mungall AJ, An J, Goya R, et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet. 2010;42:181–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Guo C, Chen LH, Huang Y, Chang CC, Wang P, Pirozzi CJ, et al. KMT2D maintains neoplastic cell proliferation and global histone H3 lysine 4 monomethylation. Oncotarget. 2013;4:2144–53.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Li G, Zan H, Xu Z, Casali P. Epigenetics of the antibody response. Trends Immunol. 2013;34:460–70.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Roh TY, Cuddapah S, Cui K, Zhao K. The genomic landscape of histone modifications in human T cells. Proc Natl Acad Sci USA. 2006;103:15782–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Banka S, Veeramachaneni R, Reardon W, Howard E, Bunstone S, Ragge N, et al. How genetically heterogeneous is Kabuki syndrome?: MLL2 testing in 116 patients, review and analyses of mutation and phenotypic spectrum. Eur J Hum Genet. 2012;20:381–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Makrythanasis P, van Bon BW, Steehouwer M, Rodríguez-Santiago B, Simpson M, Dias P, et al. MLL2 mutation detection in 86 patients with Kabuki syndrome: a genotype-phenotype study. Clin Genet. 2013;84:539–45.

    Article  CAS  PubMed  Google Scholar 

  18. Micale L, Augello B, Fusco C, Selicorni A, Loviglio MN, Silengo MC, et al. Mutation spectrum of MLL2 in a cohort of Kabuki syndrome patients. Orphanet J Rare Dis. 2011;6:38.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Cheon CK, Sohn YB, Ko JM, Lee YJ, Song JS, Moon JW, et al. Identification of KMT2D and KDM6A mutations by exome sequencing in Korean patients with Kabuki syndrome. J Hum Genet. 2014;59:321–5.

    Article  CAS  PubMed  Google Scholar 

  20. Banka S, Lederer D, Benoit V, Jenkins E, Howard E, Bunstone S, et al. Novel KDM6A (UTX) mutations and a clinical and molecular review of the X-linked Kabuki syndrome (KS2). Clin Genet. 2015;87:252–8.

    Article  CAS  PubMed  Google Scholar 

  21. Miyake N, Mizuno S, Okamoto N, Ohashi H, Shiina M, Ogata K, et al. KDM6A point mutations cause Kabuki syndrome. Hum Mutat. 2013;34:108–10.

    Article  CAS  PubMed  Google Scholar 

  22. Priolo M, Micale L, Augello B, Fusco C, Zucchetti F, Prontera P, et al. Absence of deletion and duplication of MLL2 and KDM6A genes in a large cohort of patients with Kabuki syndrome. Mol Genet Metab. 2012;107:627–9.

    Article  CAS  PubMed  Google Scholar 

  23. Dillon SC, Zhang X, Trievel RC, Cheng X. The SET-domain protein superfamily: protein lysine methyltransferases. Genome Biol. 2005;6:227.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Glaser S, Schaft J, Lubitz S, Vintersten K, van der Hoeven F, Tufteland KR, et al. Multiple epigenetic maintenance factors implicated by the loss of Mll2 in mouse development. Development. 2006;133:1423–32.

    Article  CAS  PubMed  Google Scholar 

  25. Banka S, Howard E, Bunstone S, Chandler KE, Kerr B, Lachlan K, et al. MLL2 mosaic mutations and intragenic deletion-duplications in patients with Kabuki syndrome. Clin Genet. 2013;83:467–71.

    Article  CAS  PubMed  Google Scholar 

  26. Bögershausen N, Wollnik B. Unmasking Kabuki syndrome. Clin Genet. 2013;83:201–11.

    Article  PubMed  Google Scholar 

  27. Micale L, Augello B, Maffeo C, Selicorni A, Zucchetti F, Fusco C, et al. Molecular analysis, pathogenic mechanisms, and readthrough therapy on a large cohort of Kabuki syndrome patients. Hum Mutat. 2014;35:841–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Casanova M, Selicorni A, Ferrari A. Cancer predisposition in children with Kabuki syndrome. Am J Med Genet A. 2011;155A:1504.

    Article  PubMed  Google Scholar 

  29. Hong S, Cho YW, Yu LR, Yu H, Veenstra TD, Ge K. Identification of JmjC domain-containing UTX and JMJD3 as histone H3 lysine 27 demethylases. Proc Natl Acad Sci USA. 2007;104:18439–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kim JH, Sharma A, Dhar SS, Lee SH, Gu B, Chan CH, et al. UTX and MLL4 coordinately regulate transcriptional programs for cell proliferation and invasiveness in breast cancer cells. Cancer Res. 2014;74:1705–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Van Laarhoven PM, Neitzel LR, Quintana AM, Geiger E, Zackai EH, Clouthier DE, et al. Kabuki syndrome genes KMT2D and KDM6A: functional analyses demonstrate critical roles in craniofacial, heart and brain development. Hum Mol Genet. 2015;24:4443–53.

    Article  PubMed  Google Scholar 

  32. Bjornsson HT, Benjamin JS, Zhang L, Weissman J, Gerber EE, Chen YC, et al. Histone deacetylase inhibition rescues structural and functional brain deficits in a mouse model of Kabuki syndrome. Sci Trans Med. 2014;6(256):256ra135.

    Article  Google Scholar 

  33. Ijichi O, Kawakami K, Matsuda Y, Ikarimoto N, Miyata K, Takamatsu H, Tokunaga M. A case of Kabuki make-up syndrome with EBV+ Burkitt’s lymphoma. Acta Paediatr J. 1996;38:66–8.

    Article  CAS  Google Scholar 

  34. Kawame H, Hannibal MC, Hudgins L, Pagon RA. Phenotypic spectrum and management issues in Kabuki syndrome. J Pediatr. 1999;134:480–5.

    Article  CAS  PubMed  Google Scholar 

  35. De Dios JA, Javaid AA, Ballesteros E, Metersky ML. An 18-year-old woman with Kabuki syndrome, immunoglobulin deficiency and granulomatous lymphocytic interstitial lung disease. Conn Med. 2012;76:15–8.

    PubMed  Google Scholar 

  36. Frenk NE, Kim CA, Carneiro-Sampaio M, Orii NM, de MoraesVasconcelos D. Basic evaluation of the immunocompetence of Brazilian patients with Kabuki syndrome. Pediatria (São Paulo). 2009;31:170–7.

    Google Scholar 

  37. Genevieve D, Amiel J, Viot G, Le Merrer M, Sanlaville D, Urtizberea A, et al. Atypical findings in Kabuki syndrome: report of 8 patients in a series of 20 and review of the literature. Am J Med Genet. 2004;129A:64–8.

    Article  CAS  PubMed  Google Scholar 

  38. Hostoffer RW, Bay CA, Wagner K, Venglarcik J 3rd, Sahara H, Omair E, et al. Kabuki make-up syndrome associated with an acquired hypogammaglobulinemia and anti-IgA antibodies. Clin Pediatr (Phila). 1996;35:273–6.

    Article  CAS  Google Scholar 

  39. Shah M, Bogucki B, Mavers M, deMello DE, Knutsen A. Cardiac conduction abnormalities and congenital immunodeficiency in a child with Kabuki syndrome: case report. BMC Med Gen. 2005;6:28.

    Article  Google Scholar 

  40. Chrzanowska KH, Krajewska-Walasek M, Kuś J, Michałkiewicz J, Maziarka D, Wolski JK, et al. Kabuki (Niikawa-Kuroki) syndrome associated with immunodeficiency. Clin Genet. 1998;53:308–12.

    Article  CAS  PubMed  Google Scholar 

  41. Watanabe T, Miyakawa M, Satoh M, Abe T, Oda Y. Kabuki make-up syndrome associated with chronic idiopathic thrombocytopenic purpura. Acta Paediatr Jpn. 1994;36:727–9.

    Article  CAS  PubMed  Google Scholar 

  42. McGaughran J, Aftimos S, Jefferies C, Winship I. Clinical phenotypes of nine cases of Kabuki syndrome from New Zealand. Clin Dysmorphol. 2001;10:257–62.

    Article  CAS  PubMed  Google Scholar 

  43. Armstrong L, Abd El Moneim A, Aleck K, Aughton DJ, Baumann C, Braddock SR, et al. Further delineation of Kabuki syndrome in 48 well-defined new individuals. Am J Med Genet A. 2005;132A:265–72.

    Article  PubMed  Google Scholar 

  44. Shotelersuk V, Punyashthiti R, Srivuthana S, Wacharasindhu S. Kabuki syndrome: report of six Thai children and further phenotypic and genetic delineation. Am J Med Genet. 2002;110:384–90.

    Article  PubMed  Google Scholar 

  45. Trimarchi G, Guarnaccia F, Mazzola E, Pitta R, Merla G, Zelante L, et al. Tre casi di sindrome Kabuki positivi per la mutazione del gene mll2. Riv Ital Genet Immunol Pediatr. 2012;anno IV(n.1):32.

    Google Scholar 

  46. Gidwani P, Segal E, Shanske A, Driscoll C. Chorea associated with antiphospholipid antibodies in a patient with Kabuki syndrome. Am J Med Genet A. 2007;143A:1338–41.

    Article  PubMed  Google Scholar 

  47. Giordano P, Lassandro G, Sangerardi M, Faienza MF, Valente F, Martire B. Autoimmune haematological disorders in two Italian children with Kabuki syndrome. Ital J Pediatr. 2014;40:10.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Shalev SA, Clarke LA, Koehn D, Langlois S, Zackai EH, Hall JG, et al. Long-term follow-up of three individuals with Kabuki syndrome. Am J Med Genet A. 2004;125A:191–200.

    Article  PubMed  Google Scholar 

  49. Torii Y, Yagasaki H, Tanaka H, Mizuno S, Nishio N, Muramatsu H, et al. Successful treatment with rituximab of refractory idiopathic thrombocytopenic purpura in a patient with Kabuki syndrome. Int J Hematol. 2009;90:174–6.

    Article  PubMed  Google Scholar 

  50. Nako Y, Maruyama K, Sakaguchi M, Kuroki M, Terao K, Kuribayashi T, et al. Two cases of autoimmune hemolytic anemia: a case associated with Kabuki make-up syndrome and a case with IgD as an anti-erythrocyte autoantibody. J Jpn Pediatr Soc. 1984;99:565–9.

    Google Scholar 

  51. Artigas M, Alcazar R, Bel J, Fernandez P, Javier G, Ortega E, et al. Kabuki syndrome and common variable immunodeficiency. Am J Hum Genet. 1997;61(suppl):A91.

    Google Scholar 

  52. Ewart-Toland A, Enns GM, Cox VA, Mohan GC, Rosenthal P, Golabi M. Severe congenital anomalies requiring transplantation in children with Kabuki syndrome. Am J Med Genet. 1998;80:362–7.

    Article  CAS  PubMed  Google Scholar 

  53. Ho J, Fox D, Innes AM, McLeod R, Butzner D, Johnson N, et al. Kabuki syndrome and Crohn disease in a child with familial hypocalciuric hypercalcemia. J Pediatr Endocrinol Metab. 2010;23:975–9.

    Article  CAS  PubMed  Google Scholar 

  54. Andersen MS, Menazzi S, Brun P, Cocah C, Merla G, Solari A. Clinical diagnosis of Kabuki syndrome: phenotype and associated abnormalities in two new cases. Arch Argent Pediatr. 2014;112:26–32.

    PubMed  Google Scholar 

  55. Michot C, Corsini C, Sanlaville D, Baumann C, Toutain A, Philip N, et al. Finger creases lend a hand in Kabuki syndrome. Eur J Med Genet. 2013;56:556–60.

    Article  PubMed  Google Scholar 

  56. Nishizaki N, Fujinaga S, Hirano D, Murakami H, Kamei K, Ohtomo Y, et al. Membranoproliferative glomerulonephritis type 3 associated with Kabuki syndrome. Clin Nephrol. 2014;81:369–73.

    Article  CAS  PubMed  Google Scholar 

  57. Oto J, Mano A, Nakataki E, Yamaguchi H, Inui D, Imanaka H, et al. An adult patient with Kabuki syndrome presenting with Henoch-Schönlein purpura complicated with pulmonary hemorrhage. J Anesth. 2008;22:460–3.

    Article  PubMed  Google Scholar 

  58. Zannolli R, Buoni S, Macucci F, Scarinci R, Viviano M, Orsi A, et al. Kabuki syndrome with trichrome vitiligo, ectodermal defect and hypogammaglobulinemia A and G. Brain Dev. 2007;29:373–6.

    Article  PubMed  Google Scholar 

  59. Schrander-Stumpel C, Theunissen P, Hulsmans R, Fryns JP. Kabuki make-up (Niikawa-Kuroki) syndrome in a girl presenting with vitiligo vulgaris, cleft palate, somatic and psychomotor retardation and facial dysmorphism. Genet Couns. 1993;4:71–2.

    CAS  PubMed  Google Scholar 

  60. Fujishiro M, Ogihara T, Tsukuda K, Shojima N, Fukushima Y, Kimura S, et al. A case showing an association between type 1 diabetes mellitus and Kabuki syndrome. Diabetes Res Clin Pract. 2003;60:25–31.

    Article  PubMed  Google Scholar 

  61. Lai KV, Nussbaum E, Do P, Chen J, Randhawa IS, Chin T. Congenital lung anomalies in Kabuki syndrome. J Pediatr Cong Disord. 2014;1:1–5.

    Google Scholar 

  62. Venkatesh S, Workman JL. Histone exchange, chromatin structure and the regulation of transcription. Nat Rev Mol Cell Biol. 2015;16:178–89.

    Article  CAS  PubMed  Google Scholar 

  63. Kouzarides T. Chromatin modifications and their function. Cell. 2007;128:693–705.

    Article  CAS  PubMed  Google Scholar 

  64. Kirmizis A, Bartley SM, Kuzmichev A, Margueron R, Reinberg D, Green R, et al. Silencing of human polycomb target genes is associated with methylation of histone H3 Lys 27. Genes Dev. 2004;18:1592–605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Goldberg AD, Allis CD, Bernstein E. Epigenetics: landscape takes shape. Cell. 2007;128:635–8.

    Article  CAS  PubMed  Google Scholar 

  66. Eissenberg JC, Shilatifard A. Histone H3 Lysine 4 (H3K4) methylation in development and differentiation. Dev Biol. 2010;339:240–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Wei G, Wei L, Zhu J, Zang C, Hu-Li J, Yao Z, et al. Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity. 2009;30:155–67.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Ansel KM, Djuretic I, Tanasa B, Rao A. Regulation of Th2 differentiation and IL4 locus accessibility. Annu Rev Immunol. 2006;24:607–56.

    Article  CAS  PubMed  Google Scholar 

  69. Murphy KM. Reiner SL the lineage decisions of helper T cells. Nat Rev Immunol. 2002;2:933–44.

    Article  CAS  PubMed  Google Scholar 

  70. Szabo SJ, Sullivan BM, Peng SL, Glimcher LH. Molecular mechanisms regulating Th1 immune responses. Annu Rev Immunol. 2003;21:713–58.

    Article  CAS  PubMed  Google Scholar 

  71. Weaver CT, Hatton RD, Mangan PR, Harrington LE. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol. 2007;25:821–52.

    Article  CAS  PubMed  Google Scholar 

  72. Zhu J, Paul WE. CD4 T cells: fates, functions, and faults. Blood. 2008;112:1557–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133:775–87.

    Article  CAS  PubMed  Google Scholar 

  74. Gambineri E, Perroni L, Passerini L, Bianchi L, Doglioni C, Meschi F, et al. Clinical and molecular profile of a new series of patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome: inconsistent correlation between forkhead box protein 3 expression and disease severity. J Allergy Clin Immun. 2008;122:1105–12.

    Article  CAS  PubMed  Google Scholar 

  75. Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z, et al. High-resolution profiling of histone methylations in the human genome. Cell. 2007;129:823–37.

    Article  CAS  PubMed  Google Scholar 

  76. Roh TY, Cuddapah S, Zhao K. Active chromatin domains are defined by acetylation islands revealed by genome-wide mapping. Genes Dev. 2005;19:542–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Wang Z, Zang C, Rosenfeld JA, Schones DE, Barski A, Cuddapah S, et al. Combinatorial patterns of histone acetylations and methylations in the human genome. Nat Genet. 2008;40:897–903.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Schones DE, Cui K, Cuddapah S, Roh TY, Barski A, Wang Z, et al. Dynamic regulation of nucleosome positioning in the human genome. Cell. 2008;132:887–98.

    Article  CAS  PubMed  Google Scholar 

  79. Shaknovich R, Cerchietti L, Tsikitas L, Kormaksson M, De S, Figueroa ME, et al. DNA methyltransferase 1 and DNA methylation patterning contribute to germinal center B-cell differentiation. Blood. 2011;118:3559–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Liu Z, Mai A, Sun J. Lysine acetylation regulates Bruton’s tyrosine kinase in B cell activation. J Immunol. 2010;184:244–54.

    Article  CAS  PubMed  Google Scholar 

  81. Schmidlin H, Diehl SA, Blom B. New insights into the regulation of human B-cell differentiation. Trends Immunol. 2009;30:277–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Decker T, di Magliano MP, McManus S, Sun Q, Bonifer C, Tagoh H, Busslinger M. Stepwise activation of enhancer and promoter regions of the B cell commitment gene Pax5 in early lymphopoiesis. Immunity. 2009;30:508–20.

    Article  CAS  PubMed  Google Scholar 

  83. Ramachandrareddy H, Bouska A, Shen Y, Ji M, Rizzino A, Chan WC, McKeithan TW. BCL6 promoter interacts with far upstream sequences with greatly enhanced activating histone modifications in germinal center B cells. Proc Natl Acad Sci USA. 2010;107:11930–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Jeevan-Raj BP, Robert I, Heyer V, Page A, Wang JH, Cammas F, et al. Epigenetic tethering of AID to the donor switch region during immunoglobulin class switch recombination. J Exp Med. 2011;208:1649–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Shapiro-Shelef M, Calame K. Regulation of plasma-cell development. Nat Rev Immunol. 2005;5:230–42.

    Article  CAS  PubMed  Google Scholar 

  86. McHeyzer-Williams M, Okitsu S, Wang N, McHeyzer-Williams L. Molecular programming of B cell memory. Nat Rev Immunol. 2012;12:24–34.

    CAS  Google Scholar 

  87. Portela A, Esteller M. Epigenetic modifications and human disease. Nat Biotechnol. 2010;28:1057–68.

    Article  CAS  PubMed  Google Scholar 

  88. Corneo B, Moshous D, Gungor T, Wulffraat N, Philippet P, Le Deist F, et al. Identical mutations in RAG1 or RAG2 genes leading to defective V(D)J recombinase activity can cause either T-B-severe combined immune deficiency or Omenn syndrome. Blood. 2001;97:2772–6.

    Article  CAS  PubMed  Google Scholar 

  89. Durandy A, Kracker S. Immunoglobulin class-switch recombination deficiencies. Arthritis Res Ther. 2012;14:218.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Daniel JA, Santos MA, Wang Z, Zang C, Schwab KR, Jankovic M, et al. PTIP promotes chromatin changes critical for immunoglobulin class switch recombination. Science. 2010;329:917–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Xu Z, Zan H, Pone EJ, Mai T, Casali P. Immunoglobulin class-switch DNA recombination: induction, targeting and beyond. Nat Rev Immunol. 2012;12:517–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Stanlie A, Aida M, Muramatsu M, Honjo T, Begum NA. Histone3 lysine4 trimethylation regulated by the facilitates chromatin transcription complex is critical for DNA cleavage in class switch recombination. Proc Natl Acad Sci USA. 2010;107:22190–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Kuang FL, Luo Z, Scharff MD. H3 trimethyl K9 and H3 acetyl K9 chromatin modifications are associated with class switch recombination. Proc Natl Acad Sci USA. 2009;106:5288–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Pei H, Wu X, Liu T, Yu K, Jelinek DF, Lou Z. The histone methyltransferase MMSET regulates class switch recombination. J Immunol. 2013;190:756–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Lee S, Lee DK, Dou Y, Lee J, Lee B, Kwak E, et al. Coactivator as a target gene specificity determinant for histone H3 lysine 4 methyltransferases. Proc Natl Acad Sci USA. 2006;103:15392–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Ansari KI, Mandal SS. Mixed lineage leukemia: roles in gene expression, hormone signaling and mRNA processing. FEBS J. 2010;277:1790–804.

    Article  CAS  PubMed  Google Scholar 

  97. Ansari KI, Hussain I, Shrestha B, Kasiri S, Mandal SS. HOXC6 is transcriptionally regulated via coordination of MLL histone methylase and estrogen receptor in an estrogen environment. J Mol Biol. 2011;411:334–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Guo Y, Brown C, Ortiz C, Noelle RJ. Leukocyte homing, fate, and function are controlled by retinoic acid. Physiol Rev. 2015;95:125–48.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Kovats S. Estrogen receptors regulate innate immune cells and signaling pathways. Cell Immunol. 2015;294:63–9.

    Article  CAS  PubMed  Google Scholar 

  100. Ochs H. Common variable immunodeficiency (CVID): new genetic insight and unanswered questions. Clin Exp Immunol. 2014;178:5–6.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

Thanks are due to Prof. L.D. Notarangelo for his critical reading of the manuscript and to Dr. A. Pilotta for sharing clinical data.

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    Authors and Affiliations

    1. Health Sciences Department, University of Florence, Anna Meyer Children’s University Hospital, Florence, Italy

      Stefano Stagi & Elisabetta Lapi

    2. Department of Pediatrics, Assisi Hospital, USL 1, Assisi, Italy

      Anna Virginia Gulino

    3. Institute of Pediatrics, Fondazione Policlinico Universitario Agostino Gemelli, Università Cattolica Sacro Cuore, Rome, Italy

      Donato Rigante

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    Stefano Stagi and Anna Virginia Gulino equally contributed to the preparation of this manuscript.

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    Stagi, S., Gulino, A.V., Lapi, E. et al. Epigenetic control of the immune system: a lesson from Kabuki syndrome. Immunol Res 64, 345–359 (2016). https://doi.org/10.1007/s12026-015-8707-4

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