The emerging roles of TCF4 in disease and development

Trends in Molecular Medicine

Volumn 20, Issue 6, 2014, Pages 322-331

  Forrest, Marc P ^a   Hill, Matthew J ^a   Quantock, Andrew J ^a   Martin Rendon, Enca ^b,c   Blake, Derek J ^a  

^a CARDIFF UNIVERSITY   (United Kingdom)

^b UNIVERSITY OF OXFORD   (United Kingdom)

^c JOHN RADCLIFFE HOSPITAL   (United Kingdom)

Author keywords

Epithelial mesenchymal transition; Fuchs' endothelial corneal dystrophy; Intellectual disability; Pitt Hopkins syndrome; Schizophrenia; Transcription

Indexed keywords

FIBRONECTIN; HISTONE ACETYLTRANSFERASE; IMMUNOGLOBULIN LIGHT CHAIN; SOMATOSTATIN RECEPTOR 2; TRANSCRIPTION FACTOR; TRANSCRIPTION FACTOR 4; TRANSCRIPTION FACTOR 7 LIKE 2; TRANSCRIPTION FACTOR MASH1; TRANSCRIPTION FACTOR RUNX1; TRANSCRIPTION FACTOR SNAIL; TYROSINE 3 MONOOXYGENASE; UNCLASSIFIED DRUG; UVOMORULIN; VIMENTIN; BASIC HELIX LOOP HELIX LEUCINE ZIPPER TRANSCRIPTION FACTOR; BASIC HELIX LOOP HELIX TRANSCRIPTION FACTOR; TCF4 PROTEIN, HUMAN;

ALLELE; AMINO TERMINAL SEQUENCE; COGNITION; CONGENITAL CORNEA DYSTROPHY; CORNEA DYSTROPHY; DISEASE COURSE; DISEASE PREDISPOSITION; EPITHELIAL MESENCHYMAL TRANSITION; FOLLOW UP; GENE DELETION; GENE EXPRESSION; GENE MUTATION; GENETIC ASSOCIATION; GENETIC DISORDER; GENETIC RISK; GENETIC VARIABILITY; HAPLOINSUFFICIENCY; HUMAN; INTELLECTUAL IMPAIRMENT; LIVER DISEASE; NERVE CELL DIFFERENTIATION; NONHUMAN; NUCLEAR LOCALIZATION SIGNAL; PITT HOPKIN SYNDROME; PLEIOTROPY; PRIMARY SCLEROSING CHOLANGITIS; PROTEIN EXPRESSION; PROTEIN FUNCTION; REVIEW; SCHIZOPHRENIA; SINGLE NUCLEOTIDE POLYMORPHISM; ULCERATIVE COLITIS; FACIES; GENE EXPRESSION REGULATION; GENETICS; HYPERVENTILATION; IRIDOCORNEAL ENDOTHELIAL SYNDROME; METABOLISM; MUTATION; PHYSIOLOGY;

BASIC HELIX-LOOP-HELIX LEUCINE ZIPPER TRANSCRIPTION FACTORS; BASIC HELIX-LOOP-HELIX TRANSCRIPTION FACTORS; COGNITION; EPITHELIAL-MESENCHYMAL TRANSITION; FACIES; GENE EXPRESSION REGULATION; HUMANS; HYPERVENTILATION; INTELLECTUAL DISABILITY; IRIDOCORNEAL ENDOTHELIAL SYNDROME; LIVER DISEASES; MUTATION; SCHIZOPHRENIA; TRANSCRIPTION FACTORS;

EID: 84901625426     PISSN: 14714914     EISSN: 1471499X     Source Type: Journal    
DOI: 10.1016/j.molmed.2014.01.010     Document Type: Review

References (115)

1. Stefansson H., et al. Common variants conferring risk of schizophrenia. Nature 2009, 460:744-747.
2. Henthorn P., et al. Two distinct transcription factors that bind the immunoglobulin enhancer μE5/κ2 motif. Science 1990, 247:467-470.
3. Murre C., et al. A new DNA binding and dimerization motif in immunoglobulin enhancer binding, daughterless, MyoD, and myc proteins. Cell 1989, 56:777-783.
4. Corneliussen B., et al. Helix-loop-helix transcriptional activators bind to a sequence in glucocorticoid response elements of retrovirus enhancers. J. Virol. 1991, 65:6084-6093.
5. Pscherer A., et al. The helix-loop-helix transcription factor SEF-2 regulates the activity of a novel initiator element in the promoter of the human somatostatin receptor II gene. EMBO J. 1996, 15:6680-6690.
6. Yoon S.O., Chikaraishi D.M. Isolation of two E-box binding factors that interact with the rat tyrosine hydroxylase enhancer. J. Biol. Chem. 1994, 269:18453-18462.
7. Phillips S.E. Built by association: structure and function of helix-loop-helix DNA-binding proteins. Structure 1994, 2:1-4.
8. Sepp M., et al. Functional diversity of human basic helix-loop-helix transcription factor TCF4 isoforms generated by alternative 5' exon usage and splicing. PLoS ONE 2011, 6:e22138.
9. Liu Y., et al. A splice variant of E2-2 basic helix-loop-helix protein represses the brain-specific fibroblast growth factor 1 promoter through the binding to an imperfect E-box. J. Biol. Chem. 1998, 273:19269-19276.
10. Skerjanc I.S., et al. A splice variant of the ITF-2 transcript encodes a transcription factor that inhibits MyoD activity. J. Biol. Chem. 1996, 271:3555-3561.
11. Sobrado V.R., et al. The class I bHLH factors E2-2A and E2-2B regulate EMT. J. Cell Sci. 2009, 122:1014-1024.
12. Petropoulos H., Skerjanc I.S. Analysis of the inhibition of MyoD activity by ITF-2B and full-length E12/E47. J. Biol. Chem. 2000, 275:25095-25101.
13. Lu Y., et al. A negative regulatory element-dependent inhibitory role of ITF2B on IL-2 receptor α gene. Biochem. Biophys. Res. Commun. 2005, 336:142-149.
14. Furumura M., et al. Involvement of ITF2 in the transcriptional regulation of melanogenic genes. J. Biol. Chem. 2001, 276:28147-28154.
15. de Pontual L., et al. Mutational, functional, and expression studies of the TCF4 gene in Pitt-Hopkins syndrome. Hum. Mutat. 2009, 30:669-676.
16. Forrest M., et al. Functional analysis of TCF4 missense mutations that cause Pitt-Hopkins syndrome. Hum. Mutat. 2012, 33:1676-1686.
17. Massari M.E., et al. A conserved motif present in a class of helix-loop-helix proteins activates transcription by direct recruitment of the SAGA complex. Mol. Cell 1999, 4:63-73.
18. Bayly R., et al. E2A-PBX1 interacts directly with the KIX domain of CBP/p300 in the induction of proliferation in primary hematopoietic cells. J. Biol. Chem. 2004, 279:55362-55371.
19. Zhang J., et al. E protein silencing by the leukemogenic AML1-ETO fusion protein. Science 2004, 305:1286-1289.
20. Voronova A., Baltimore D. Mutations that disrupt DNA binding and dimer formation in the E47 helix-loop-helix protein map to distinct domains. Proc. Natl. Acad. Sci. U.S.A. 1990, 87:4722-4726.
21. Ellenberger T., et al. Crystal structure of transcription factor E47: E-box recognition by a basic region helix-loop-helix dimer. Genes Dev. 1994, 8:970-980.
22. Longo A., et al. Crystal structure of E47-NeuroD1/β2 bHLH domain-DNA complex: heterodimer selectivity and DNA recognition. Biochemistry 2008, 47:218-229.
23. Goldfarb A.N., et al. Identification of a highly conserved module in E proteins required for in vivo helix-loop-helix dimerization. J. Biol. Chem. 1998, 273:2866-2873.
24. Blake D.J., et al. TCF4, schizophrenia, and Pitt-Hopkins syndrome. Schizophr. Bull. 2010, 36:443-447.
25. Teachenor R., et al. Biochemical and phosphoproteomic analysis of the helix-loop-helix protein E47. Mol. Cell. Biol. 2012, 32:1671-1682.
26. Corneliussen B., et al. Calcium/calmodulin inhibition of basic-helix-loop-helix transcription factor domains. Nature 1994, 368:760-764.
27. Onions J., et al. Basic helix-loop-helix protein sequences determining differential inhibition by calmodulin and S-100 proteins. J. Biol. Chem. 1997, 272:23930-23937.
28. Larsson G., et al. A novel target recognition revealed by calmodulin in complex with the basic helix-loop-helix transcription factor SEF2-1/E2-2. Protein Sci. 2001, 10:169-186.
29. Larsson G., et al. Backbone dynamics of a symmetric calmodulin dimer in complex with the calmodulin-binding domain of the basic-helix-loop-helix transcription factor SEF2-1/E2-2: a highly dynamic complex. Biophys. J. 2005, 89:1214-1226.
30. Hauser J., et al. B-cell receptor activation inhibits AID expression through calmodulin inhibition of E-proteins. Proc. Natl. Acad. Sci. U.S.A. 2008, 105:1267-1272.
31. Hauser J., et al. Calcium regulation of myogenesis by differential calmodulin inhibition of basic helix-loop-helix transcription factors. Mol. Biol. Cell 2008, 19:2509-2519.
32. Kee B.L. E and ID proteins branch out. Nat. Rev. Immunol. 2009, 9:175-184.
33. Murre C. Helix-loop-helix proteins and lymphocyte development. Nat. Immunol. 2005, 6:1079-1086.
34. Zhuang Y., et al. B-lymphocyte development is regulated by the combined dosage of three basic helix-loop-helix genes, E2A, E2-2, and HEB. Mol. Cell. Biol. 1996, 16:2898-2905.
35. Bergqvist I., et al. The basic helix-loop-helix transcription factor E2-2 is involved in T lymphocyte development. Eur. J. Immunol. 2000, 30:2857-2863.
36. Reizis B. Regulation of plasmacytoid dendritic cell development. Curr. Opin. Immunol. 2010, 22:206-211.
37. Ghosh H.S., et al. Continuous expression of the transcription factor e2-2 maintains the cell fate of mature plasmacytoid dendritic cells. Immunity 2010, 33:905-916.
38. Cisse B., et al. Transcription factor E2-2 is an essential and specific regulator of plasmacytoid dendritic cell development. Cell 2008, 135:37-48.
39. Hacker C., et al. Transcriptional profiling identifies Id2 function in dendritic cell development. Nat. Immunol. 2003, 4:380-386.
40. Li H.S., et al. The signal transducers STAT5 and STAT3 control expression of Id2 and E2-2 during dendritic cell development. Blood 2012, 120:4363-4373.
41. Banchereau J., Pascual V. Type I interferon in systemic lupus erythematosus and other autoimmune diseases. Immunity 2006, 25:383-392.
42. Cano A., Portillo F. An emerging role for class I bHLH E2-2 proteins in EMT regulation and tumor progression. Cell Adh. Migr. 2010, 4:56-60.
43. Lim J., Thiery J.P. Epithelial-mesenchymal transitions: insights from development. Development 2012, 139:3471-3486.
44. Kalluri R., Weinberg R.A. The basics of epithelial-mesenchymal transition. J. Clin. Invest. 2009, 119:1420-1428.
45. Perez-Moreno M.A., et al. A new role for E12/E47 in the repression of E-cadherin expression and epithelial-mesenchymal transitions. J. Biol. Chem. 2001, 276:27424-27431.
46. Bolos V., et al. The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with Snail and E47 repressors. J. Cell Sci. 2003, 116:499-511.
47. Cano A., et al. The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat. Cell Biol. 2000, 2:76-83.
48. Moreno-Bueno G., et al. Genetic profiling of epithelial cells expressing E-cadherin repressors reveals a distinct role for Snail, Slug, and E47 factors in epithelial-mesenchymal transition. Cancer Res. 2006, 66:9543-9556.
49. Forrest M.P., et al. Knockdown of human TCF4 affects multiple signaling pathways involved in cell survival, epithelial to mesenchymal transition and neuronal differentiation. PLoS ONE 2013, 8:e73169.
50. Nieto M.A. The ins and outs of the epithelial to mesenchymal transition in health and disease. Annu. Rev. Cell Dev. Biol. 2011, 27:347-376.
51. Bertrand N., et al. Proneural genes and the specification of neural cell types. Nat. Rev. Neurosci. 2002, 3:517-530.
52. Powell L.M., Jarman A.P. Context dependence of proneural bHLH proteins. Curr. Opin. Genet. Dev. 2008, 18:411-417.
53. Flora A., et al. The E-protein Tcf4 interacts with Math1 to regulate differentiation of a specific subset of neuronal progenitors. Proc. Natl. Acad. Sci. U.S.A. 2007, 104:15382-15387.
54. Amiel J., et al. Mutations in TCF4, encoding a class I basic helix-loop-helix transcription factor, are responsible for Pitt-Hopkins syndrome, a severe epileptic encephalopathy associated with autonomic dysfunction. Am. J. Hum. Genet. 2007, 80:988-993.
55. Pitt D., Hopkins I. A syndrome of mental retardation, wide mouth and intermittent overbreathing. Aust. Paediatr. J. 1978, 14:182-184.
56. Zweier C., et al. Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome). Am. J. Hum. Genet. 2007, 80:994-1001.
57. Sepp M., et al. Pitt-Hopkins syndrome-associated mutations in TCF4 lead to variable impairment of the transcription factor function ranging from hypomorphic to dominant-negative effects. Hum. Mol. Genet. 2012, 21:2873-2888.
58. Brockschmidt A., et al. Severe mental retardation with breathing abnormalities (Pitt-Hopkins syndrome) is caused by haploinsufficiency of the neuronal bHLH transcription factor TCF4. Hum. Mol. Genet. 2007, 16:1488-1494.
59. Zweier C., et al. CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in Drosophila. Am. J. Hum. Genet. 2009, 85:655-666.
60. Alarcon M., et al. Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. Am. J. Hum. Genet. 2008, 82:150-159.
61. Kirov G., et al. Neurexin 1 (NRXN1) deletions in schizophrenia. Schizophr. Bull. 2009, 35:851-854.
62. Talkowski M.E., et al. Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries. Cell 2012, 149:525-537.
63. Rauch A., et al. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet 2012, 380:1674-1682.
64. Hamdan F.F., et al. Parent-child exome sequencing identifies a de novo truncating mutation in TCF4 in non-syndromic intellectual disability. Clin. Genet. 2013, 83:198-200.
65. Sullivan P.F., et al. Genetic architectures of psychiatric disorders: the emerging picture and its implications. Nat. Rev. Genet. 2012, 13:537-551.
66. Ripke S., et al. Genome-wide association study identifies five new schizophrenia loci. Nat. Genet. 2011, 43:969-976.
67. Lewis D.A., Levitt P. Schizophrenia as a disorder of neurodevelopment. Annu. Rev. Neurosci. 2002, 25:409-432.
68. Insel T.R. Rethinking schizophrenia. Nature 2010, 468:187-193.
69. Wright C., et al. Potential impact of miR-137 and its targets in schizophrenia. Front. Genet. 2013, 4:58.
70. Williams H.J., et al. Association between TCF4 and schizophrenia does not exert its effect by common nonsynonymous variation or by influencing cis-acting regulation of mRNA expression in adult human brain. Am. J. Med. Genet. B: Neuropsychiatr. Genet. 2011, 156B:781-784.
71. Hu X., et al. A survey of rare coding variants in candidate genes in schizophrenia by deep sequencing. Mol. Psychiatry 2013, 10.1038/mp.2013.131.
72. Pastinen T. Genome-wide allele-specific analysis: insights into regulatory variation. Nat. Rev. Genet. 2010, 11:533-538.
73. Buonocore F., et al. Effects of cis-regulatory variation differ across regions of the adult human brain. Hum. Mol. Genet. 2010, 19:4490-4496.
74. Hill M.J., Bray N.J. Evidence that schizophrenia risk variation in the ZNF804A gene exerts its effects during fetal brain development. Am. J. Psychiatry 2012, 169:1301-1308.
75. Quednow B.B., et al. Transcription factor 4 (TCF4) and schizophrenia: integrating the animal and the human perspective. Cell. Mol. Life Sci. 2014, 10.1007/s00018-013-1553-4.
76. Toulopoulouand T., Murray R.M. Verbal memory deficit in patients with schizophrenia: an important future target for treatment. Expert Rev. Neurother. 2004, 4:43-52.
77. Lennertz L., et al. Novel schizophrenia risk gene TCF4 influences verbal learning and memory functioning in schizophrenia patients. Neuropsychobiology 2011, 63:131-136.
78. Wirgenes K.V., et al. TCF4 sequence variants and mRNA levels are associated with neurodevelopmental characteristics in psychotic disorders. Transl. Psychiatry 2012, 2:e112.
79. Quednow B.B., et al. The schizophrenia risk allele C of the TCF4 rs9960767 polymorphism disrupts sensorimotor gating in schizophrenia spectrum and healthy volunteers. J. Neurosci. 2011, 31:6684-6691.
80. Braff D.L., Geyer M.A. Sensorimotor gating and schizophrenia. Human and animal model studies. Arch. Gen. Psychiatry 1990, 47:181-188.
81. Brzozka M.M., et al. Cognitive and sensorimotor gating impairments in transgenic mice overexpressing the schizophrenia susceptibility gene Tcf4 in the brain. Biol. Psychiatry 2010, 68:33-40.
82. Quednow B.B., et al. Schizophrenia risk polymorphisms in the TCF4 gene interact with smoking in the modulation of auditory sensory gating. Proc. Natl. Acad. Sci. U.S.A. 2012, 109:6271-6276.
83. Lijffijt M., et al. P50, N100, and P200 sensory gating: relationships with behavioral inhibition, attention, and working memory. Psychophysiology 2009, 46:1059-1068.
84. Ellinghaus D., et al. Genome-wide association analysis in Primary sclerosing cholangitis and ulcerative colitis identifies risk loci at GPR35 and TCF4. Hepatology 2013, 58:1074-1083.
85. Aron J.H., Bowlus C.L. The immunobiology of primary sclerosing cholangitis. Semin. Immunopathol. 2009, 31:383-397.
86. Liu J.Z., et al. Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis. Nat. Genet. 2013, 45:670-675.
87. Baratz K.H., et al. E2-2 protein and Fuchs's corneal dystrophy. N. Engl. J. Med. 2010, 363:1016-1024.
88. Jurkunas U.V., et al. Increased clusterin expression in Fuchs' endothelial dystrophy. Invest. Ophthalmol. Vis. Sci. 2008, 49:2946-2955.
89. Igo R.P., et al. Differing roles for TCF4 and COL8A2 in central corneal thickness and fuchs endothelial corneal dystrophy. PLoS One 2012, 7:e46742. PMID: 23110055.
90. Wieben E.D., et al. A common trinucleotide repeat expansion within the transcription factor 4 (TCF4, E2-2) gene predicts Fuchs corneal dystrophy. PLoS ONE 2012, 7:e49083.
91. Mootha V.V., et al. Association and familial segregation of CTG18.1 trinucleotide repeat expansion of TCF4 gene in Fuchs' endothelial corneal dystrophy. Invest. Ophthalmol. Vis. Sci. 2014, 55:33-42.
92. Schmedt T., et al. Molecular bases of corneal endothelial dystrophies. Exp. Eye Res. 2012, 95:24-34.
93. Riazuddin S.A., et al. Mutations in AGBL1 cause dominant late-onset Fuchs corneal dystrophy and alter protein-protein interaction with TCF4. Am. J. Hum. Genet. 2013, 93:758-764.
94. Massari M.E., Murre C. Helix-loop-helix proteins: regulators of transcription in eucaryotic organisms. Mol. Cell. Biol. 2000, 20:429-440.
95. Bain G., Murre C. The role of E-proteins in B- and T-lymphocyte development. Semin. Immunol. 1998, 10:143-153.
96. Murre C., et al. Interactions between heterologous helix-loop-helix proteins generate complexes that bind specifically to a common DNA sequence. Cell 1989, 58:537-544.
97. Benezra R., et al. The protein Id: a negative regulator of helix-loop-helix DNA binding proteins. Cell 1990, 61:49-59.
98. Sun X.H., et al. Id proteins Id1 and Id2 selectively inhibit DNA binding by one class of helix-loop-helix proteins. Mol. Cell. Biol. 1991, 11:5603-5611.
99. Iavarone A., Lasorella A. ID proteins as targets in cancer and tools in neurobiology. Trends Mol. Med. 2006, 12:588-594.
100. Akazawa C., et al. Molecular characterization of a rat negative regulator with a basic helix-loop-helix structure predominantly expressed in the developing nervous system. J. Biol. Chem. 1992, 267:21879-21885.
101. Ohsako S., et al. Hairy function as a DNA-binding helix-loop-helix repressor of Drosophila sensory organ formation. Genes Dev. 1994, 8:2743-2755.
102. Sasai Y., et al. Two mammalian helix-loop-helix factors structurally related to Drosophila hairy and Enhancer of split. Genes Dev. 1992, 6:2620-2634.
103. Kageyama R., et al. The Hes gene family: repressors and oscillators that orchestrate embryogenesis. Development 2007, 134:1243-1251.
104. Acloque H., et al. Epithelial-mesenchymal transitions: the importance of changing cell state in development and disease. J. Clin. Invest. 2009, 119:1438-1449.
105. Gotz M., Huttner W.B. The cell biology of neurogenesis. Nat. Rev. Mol. Cell Biol. 2005, 6:777-788.
106. Pacary E., et al. Crucial first steps: the transcriptional control of neuron delamination. Neuron 2012, 74:209-211.
107. Castro D.S., Guillemot F. Old and new functions of proneural factors revealed by the genome-wide characterization of their transcriptional targets. Cell Cycle 2011, 10:4026-4031.
108. Farah M.H., et al. Generation of neurons by transient expression of neural bHLH proteins in mammalian cells. Development 2000, 127:693-702.
109. Heng J.I., et al. Neurogenin 2 controls cortical neuron migration through regulation of Rnd2. Nature 2008, 455:114-118.
110. Ge W., et al. Coupling of cell migration with neurogenesis by proneural bHLH factors. Proc. Natl. Acad. Sci. U.S.A. 2006, 103:1319-1324.
111. Schwab M.H., et al. Neuronal basic helix-loop-helix proteins (NEX and BETA2/Neuro D) regulate terminal granule cell differentiation in the hippocampus. J. Neurosci. 2000, 20:3714-3724.
112. Steinberg S., et al. Common variants at VRK2 and TCF4 conferring risk of schizophrenia. Hum. Mol. Genet. 2011, 20:4076-4081.
113. Aberg K.A., et al. A comprehensive family-based replication study of schizophrenia genes. JAMA Psychiatry 2013, 70:573-581.
114. Purcell S.M., et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 2009, 460:748-752. International Schizophrenia Consortium.
115. Wojciechowska M., Krzyzosiak W.J. Cellular toxicity of expanded RNA repeats: focus on RNA foci. Hum. Mol. Genet. 2011, 20:3811-3821.