Transcriptional derepression as a cause of genetic diseases

Current Opinion in Genetics and Development

Volumn 13, Issue 3, 2003, Pages 239-245

  Gabellini, Davide ^a   Tupler, Rossella ^a,b   Green, Michael R ^a  

^a UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL   (United States)

^b UNIVERSITY OF PAVIA   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

BECKWITH WIEDEMANN SYNDROME; CENTROMERE; DENTATORUBROPALLIDOLUYSIAN ATROPHY; DIABETES MELLITUS; DNA TRANSCRIPTION; FACE MALFORMATION; FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY; GENE EXPRESSION; GENE TARGETING; GENETIC DISORDER; HUMAN; IMMUNE DEFICIENCY; MOLECULAR BIOLOGY; MUTATION; NONHUMAN; OBESITY; PRIORITY JOURNAL; REGULATORY MECHANISM; RETT SYNDROME; REVIEW; RNA TRANSCRIPTION; TRANSCRIPTION INITIATION;

EID: 0038350652     PISSN: 0959437X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0959-437X(03)00050-9     Document Type: Review

References (55)

1. Lee T.I., Young R.A. Transcription of eukaryotic protein-coding genes. Ann. Rev. Genet. 34:2000;77-137.
2. Jepsen K., Rosenfeld M.G. Biological roles and mechanistic actions of co-repressor complexes. J. Cell Sci. 115:2002;689-698 This review summarizes recent advances in understanding the biological importance of transcriptional co-repressor proteins, as revealed by studies of genetically engineered mice and human diseases.
3. Semenza GL: Transcription Factors and Human Disease, vol 37. Edited by Semenza GL. New York: Oxford University Press; 1998.
4. Robertson K.D., Wolffe A.P. DNA methylation in health and disease. Nat. Rev. Genet. 1:2000;11-19.
5. Paulsen M., Ferguson-Smith A.C. DNA methylation in genomic imprinting, development, and disease. J. Pathol. 195:2001;97-110.
6. Maraschio P., Zuffardi O., Dalla Fior T., Tiepolo L. Immunodeficiency, centromeric heterochromatin instability of chromosomes 1, 9, and 16, and facial anomalies: the ICF syndrome. J. Med. Genet. 25:1988;173-180.
7. Smeets D.F., Moog U., Weemaes C.M., Vaes-Peeters G., Merkx G.F., Niehof J.P., Hamers G. ICF syndrome: a new case and review of the literature. Hum. Genet. 94:1994;240-246.
8. Jeanpierre M., Turleau C., Aurias A., Prieur M., Ledeist F., Fischer A., Viegas-Pequignot E. An embryonic-like methylation pattern of classical satellite DNA is observed in ICF syndrome. Hum. Mol. Genet. 2:1993;731-735.
9. Okano M., Bell D.W., Haber D.A., Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell. 99:1999;247-257.
10. Xu G.L., Bestor T.H., Bourc'his D., Hsieh C.L., Tommerup N., Bugge M., Hulten M., Qu X., Russo J.J., Viegas-Pequignot E. Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature. 402:1999;187-191.
11. Hansen R.S., Wijmenga C., Luo P., Stanek A.M., Canfield T.K., Weemaes C.M., Gartler S.M. The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome. Proc. Natl. Acad Sci. USA. 96:1999;14412-14417.
12. Ehrlich M., Buchanan K.L., Tsien F., Jiang G., Sun B., Uicker W., Weemaes C.M., Smeets D., Sperling K., Belohradsky B.H.et al. DNA methyltransferase 3B mutations linked to the ICF syndrome cause dysregulation of lymphogenesis genes. Hum. Mol. Genet. 10:2001;2917-2931 This paper reports the results of microarray expression analysis on B-cell lymphoblastoid cell lines from normal and ICF patients with diverse DNMT3B mutations. Among the genes showing consistent and significant ICF-specific changes in RNA levels, several play a role in immune function. Surprisingly, promoters of differentially expressed genes showed no differences in DNA methylation. These data suggest that DNMT3B mutations in ICF syndrome result in lymphogenesis-associated gene dysregulation by indirect effects on gene expression.
13. Shahbazian M.D., Zoghbi H.Y. Rett syndrome and MeCP2: linking epigenetics and neuronal function. Am. J. Hum. Genet. 71:2002;1259-1272 A comprehensive review about Rett syndrome and MECP2.
14. Amir R.E., Van den Veyver I.B., Wan M., Tran C.Q., Francke U., Zoghbi H.Y. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat. Genet. 23:1999;185-188.
15. Kokura K., Kaul S.C., Wadhwa R., Nomura T., Khan M.M., Shinagawa T., Yasukawa T., Colmenares C., Ishii S. The Ski protein family is required for MeCP2-mediated transcriptional repression. J. Biol. Chem. 276:2001;34115-34121.
16. Jones P.L., Veenstra G.J., Wade P.A., Vermaak D., Kass S.U., Landsberger N., Strouboulis J., Wolffe A.P. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat. Genet. 19:1998;187-191.
17. Nan X., Ng H.H., Johnson C.A., Laherty C.D., Turner B.M., Eisenman R.N., Bird A. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature. 393:1998;386-389.
18. ••].
19. ••].
20. ••] report the generation of animal models of Rett syndrome. Significantly, the deficiency of MECP2 specifically in neurons is sufficient to cause neuronal dysfunction with a symptomatic manifestation similar to Rett syndrome. In addition, histone H3 is hyperacetylated, suggesting that gene expression may be misregulated in this disease.
21. Tudor M., Akbarian S., Chen R.Z., Jaenisch R. Transcriptional profiling of a mouse model for Rett syndrome reveals subtle transcriptional changes in the brain. Proc. Natl. Acad Sci. USA. 99:2002;15536-15541 Biochemical data suggest that MECP2 acts as a global transcriptional repressor, predicting that MECP2 mutant mice should have genome-wide transcriptional deregulation. Here, this hypothesis has been tested by global transcriptional profiling on brain tissues of wild-type and MECP2 mutant mice. The results of numerous microarray analyses revealed no dramatic changes in transcription, even in mice displaying overt disease symptoms. This result suggests that MECP2 deficiency leads to subtle gene expression changes in mutant brains, which may be associated with the phenotypic changes observed.
22. Naito H., Oyanagi S. Familial myoclonus epilepsy and choreoathetosis: hereditary dentatorubral-pallidoluysian atrophy. Neurology. 32:1982;798-807.
23. Koide R., Ikeuchi T., Onodera O., Tanaka H., Igarashi S., Endo K., Takahashi H., Kondo R., Ishikawa A., Hayashi T.et al. Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA). Nat. Genet. 6:1994;9-13.
24. Wood J.D., Nucifora F.C. Jr., Duan K., Zhang C., Wang J., Kim Y., Schilling G., Sacchi N., Liu J.M., Ross C.A. Atrophin-1, the dentato-rubral and pallido-luysian atrophy gene product, interacts with ETO/MTG8 in the nuclear matrix and represses transcription. J. Cell Biol. 150:2000;939-948.
25. Zhang S., Xu L., Lee J., Xu T. Drosophila atrophin homolog functions as a transcriptional corepressor in multiple developmental processes. Cell. 108:2002;45-56 This paper demonstrates that Drosophila Atrophin is required for diverse developmental processes, including early embryonic patterning. Furthermore, both human Atrophin-1 and Drosophila Atrophin repress transcription in vivo when tethered to DNA, and poly-Q expansion in Atrophin-1 reduces this repressive activity.
26. Maher E.R., Reik W. Beckwith-Wiedemann syndrome: imprinting in clusters revisited. J. Clin. Invest. 105:2000;247-252.
27. Weksberg R., Shen D.R., Fei Y.L., Song Q.L., Squire J. Disruption of insulin-like growth factor 2 imprinting in Beckwith-Wiedemann syndrome. Nat. Genet. 5:1993;143-150.
28. Joyce J.A., Lam W.K., Catchpoole D.J., Jenks P., Reik W., Maher E.R., Schofield P.N. Imprinting of IGF2 and H19: lack of reciprocity in sporadic Beckwith-Wiedemann syndrome. Hum. Mol. Genet. 6:1997;1543-1548.
29. Sun F.L., Dean W.L., Kelsey G., Allen N.D., Reik W. Transactivation of Igf2 in a mouse model of Beckwith-Wiedemann syndrome. Nature. 389:1997;809-815.
30. Thorvaldsen J.L., Duran K.L., Bartolomei M.S. Deletion of the H19 differentially methylated domain results in loss of imprinted expression of H19 and Igf2. Genes Dev. 12:1998;3693-3702.
31. Bell A.C., Felsenfeld G. Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene. Nature. 405:2000;482-485.
32. Hark A.T., Schoenherr C.J., Katz D.J., Ingram R.S., Levorse J.M., Tilghman S.M. CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus. Nature. 405:2000;486-489.
33. Hamatani T., Sasaki H., Ishihara K., Hida N., Maruyama T., Yoshimura Y., Hata J., Umezawa A. Epigenetic mark sequence of the H19 gene in human sperm. Biochim. Biophys. Acta. 1518:2001;137-144.
34. Schoenherr C.J., Levorse J.M., Tilghman S.M. CTCF maintains differential methylation at the Igf2/H19 locus. Nat. Genet. 33:2003;66-69 This study constitutes the first in vivo demonstration of the multiple functions of CTCF in the imprinting control region (ICR). Using mice that harbor point mutations in CTCF binding sites, the authors show that CTCF binding is required to maintain, but not establish, the differential methylation of the ICR.
35. Kissel J.T. Facioscapulohumeral dystrophy. Semin. Neurol. 19:1999;35-43.
36. Sarfarazi M., Wijmenga C., Upadhyaya M., Weiffenbach B., Hyser C., Mathews K., Murray J., Gilbert J., Pericak-Vance M., Lunt P. Regional mapping of facioscapulohumeral muscular dystrophy gene on 4q35: combined analysis of an international consortium. Am. J. Hum. Genet. 51:1992;396-403.
37. Wijmenga C., Hewitt J.E., Sandkuijl L.A., Clark L.N., Wright T.J., Dauwerse H.G., Gruter A.M., Hofker M.H., Moerer P., Williamson R. Chromosome 4q DNA rearrangements associated with facioscapulohumeral muscular dystrophy. Nat. Genet. 2:1992;26-30.
38. Goto K., Song M.D., Lee J.H., Arahata K. Genetic analysis of facioscapulohumeral muscular dystrophy (FSHD). Rinsho Shinkeigaku. 35:1995;1416-1418.
39. Lunt P.W., Jardine P.E., Koch M.C., Maynard J., Osborn M., Williams M., Harper P.S., Upadhyaya M. Correlation between fragment size at D4F104S1 and age at onset or at wheelchair use, with a possible generational effect, accounts for much phenotypic variation in 4q35-facioscapulohumeral muscular dystrophy (FSHD). Hum. Mol. Genet. 4:1995;951-958.
40. Zatz M., Marie S.K., Passos-Bueno M.R., Vainzof M., Campiotto S., Cerqueira A., Wijmenga C., Padberg G., Frants R. High proportion of new mutations and possible anticipation in Brazilian facioscapulohumeral muscular dystrophy families. Am. J. Hum. Genet. 56:1995;99-105.
41. Tawil R., Forrester J., Griggs R.C., Mendell J., Kissel J., McDermott M., King W., Weiffenbach B., Figlewicz D. Evidence for anticipation and association of deletion size with severity in facioscapulohumeral muscular dystrophy. The FSH-DY Group. Ann. Neurol. 39:1996;744-748.
42. Hsu Y.D., Kao M.C., Shyu W.C., Lin J.C., Huang N.E., Sun H.F., Yang K.D., Tsao W.L. Application of chromosome 4q35-qter marker (pFR-1) for DNA rearrangement of facioscapulohumeral muscular dystrophy patients in Taiwan. J. Neurol. Sci. 149:1997;73-79.
43. Ricci E., Galluzzi G., Deidda G., Cacurri S., Colantoni L., Merico B., Piazzo N., Servidei S., Vigneti E., Pasceri V.et al. Progress in the molecular diagnosis of facioscapulohumeral muscular dystrophy and correlation between the number of KpnI repeats at the 4q35 locus and clinical phenotype. Ann. Neurol. 45:1999;751-757.
44. Gabellini D., Green M.R., Tupler R. Inappropriate gene activation in FSHD: a repressor complex binds a chromosomal repeat deleted in dystrophic muscle. Cell. 110:2002;339-348 In addition to revealing the molecular mechanism of FSHD, this paper establishes a role for DNA repetitive elements in regulating gene expression and in causing a human disorder. FSHD patients carry deletions of an integral number of tandem 3.3 kilobase repeats, termed D4Z4, located on chromosome 4q35. Gene-expression analysis showed that 4q35 genes located upstream of D4Z4 are inappropriately over-expressed specifically in FSHD muscle. An element within D4Z4 specifically binds a multi-protein complex and mediates transcriptional repression of 4q35 genes. On the basis of these results it has been proposed that deletion of D4Z4 leads to the inappropriate transcriptional de-repression of 4q35 genes resulting in disease.
45. Pugliese A., Miceli D. The insulin gene in diabetes. Diabetes Metab. Res. Rev. 18:2002;13-25 An informative review about the biological mechanisms by which misregulation of insulin gene expression contributes to diabetes.
46. Bell G.I., Horita S., Karam J.H. A polymorphic locus near the human insulin gene is associated with insulin-dependent diabetes mellitus. Diabetes. 33:1984;176-183.
47. Kennedy G.C., German M.S., Rutter W.J. The minisatellite in the diabetes susceptibility locus IDDM2 regulates insulin transcription. Nat. Genet. 9:1995;293-298.
48. Paquette J., Giannoukakis N., Polychronakos C., Vafiadis P., Deal C. The INS 5′ variable number of tandem repeats is associated with IGF2 expression in humans. J. Biol. Chem. 273:1998;14158-14164.
49. Bell G.I., Selby M.J., Rutter W.J. The highly polymorphic region near the human insulin gene is composed of simple tandemly repeating sequences. Nature. 295:1982;31-35.
50. Lucassen A.M., Screaton G.R., Julier C., Elliott T.J., Lathrop M., Bell J.I. Regulation of insulin gene expression by the IDDM associated, insulin locus haplotype. Hum. Mol. Genet. 4:1995;501-506.
51. Bennett S.T., Lucassen A.M., Gough S.C., Powell E.E., Undlien D.E., Pritchard L.E., Merriman M.E., Kawaguchi Y., Dronsfield M.J., Pociot F.et al. Susceptibility to human type 1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus. Nat. Genet. 9:1995;284-292.
52. Lucassen A.M., Julier C., Beressi J.P., Boitard C., Froguel P., Lathrop M., Bell J.I. Susceptibility to insulin dependent diabetes mellitus maps to a 4.1 kb segment of DNA spanning the insulin gene and associated VNTR. Nat. Genet. 4:1993;305-310.
53. Le Stunff C., Fallin D., Bougneres P. Paternal transmission of the very common class I INS VNTR alleles predisposes to childhood obesity. Nat. Genet. 29:2001;96-99 The results presented in this paper suggest that increased in utero expression of paternal insulin or IGF2 genes, due to inheritance of the class I insulin-gene VNTR allele, may predispose offspring to postnatal fat deposition.
54. Lagos-Quintana M., Rauhut R., Yalcin A., Meyer J., Lendeckel W., Tuschl T. Identification of tissue-specific microRNAs from mouse. Curr. Biol. 12:2002;735-739 In this paper, it is reported that in several tissues a single microRNA (miRNA) dominates the population of expressed miRNAs. This suggests a role for these miRNAs in tissue specification or cell lineage decisions.
55. Arney K.L. H19 and Igf2 - enhancing the confusion? Trends Genet. 19:2003;17-23 As described in this review, a complex interactive network of regulatory elements is required for correct imprinting of the H19/IGF2 genes in the different tissues of the body.