The sins of the fathers and mothers: genomic imprinting in mammalian development.

摘要: That some imprinting is dependent upon a signal capable of acting over large distance follows from studies subset PWS and AS patients (Figure 3Figure 3). These have small microdeletions the promoter first exon SNRPN gene, which result in loss expression that as well at least three paternally expressed genes lie far 1 Mb away on chromosome (Buiting et al. 1995xInherited Angelman Prader-Willi syndromes define an centre human 15. Buiting, K, Saitoh, S, Gross, Dittrich, B, Schwartz, Nicholls, R.D, Horsthemke, B. Nat. Genet. 1995; 9: 395–400Crossref | PubMed Scopus (436)See all ReferencesBuiting 1995). Furthermore, paternal harbors such mutation displays methylation pattern wild-type maternal chromosome. Even more surprising finding deletions just upstream lead to by presumably eliminating UBE3A, possibly other maternally hundreds kilobases telomeric SNRPN.Figure 3Imprinting Syndrome Region(A) The structure gene positions “BD” exons are depicted, with transcriptional start sites indicated horizontal arrows. Below diagram extent minimal region held common among microdeletion families. Adapted Dittrich 1996xImprint switching 15 may involve alternative transcripts gene. Korn, Rickard, Buxton, J, Poustka, A, Winterpacht, Zabel, 1996; 14: 163–170Crossref (180)See ReferencesDittrich 1996.(B) rectangles, transcribed alleles filled purple (paternal expression) or red (maternal expression). deleted blue arrow. germline epigenetic mark vertical lines, whereas DNA be consequence gray lines.(C) functional deletion question indicates UBE3A has not been verified PWS.View Large Image View Hi-Res Download PowerPoint SlideHow do these cis-acting act distances? answer clear, but each case, primary gametic signal, status promoter, able propagate changes and/or chromatin throughout (5xInherited References, 12xImprint References). In soma, transcription could required unmethylated open conformation chromosome, akin model Figure 2FFigure 2F. Maternal propagation different, closed methylated state. There precedence for ability CpG island, like inhibit non-island sequences distance, although distances very much greater than any tested experimentally (4xSp1 elements protect island de novo methylation. Brandeis, M, Frank, D, Keshet, I, Siegfried, Z, Mendelsohn, Nemes, Temper, V, Razin, Cedar, H. Nature. 1994; 371: 435–438Crossref (539)See 35xSp1 mouse aprt prevent island. Macleod, Charlton, Mullins, Bird, A.P. Genes Dev. 8: 2282–2292Crossref PubMedSee References).The foregoing attributes key function analysis sporadic nondeletion implied also germ line erase imprint 6xSporadic defects syndrome (implications imprint-switch models, genetic counseling, prenatal diagnosis) . Lich, C, Farber, Buchholz, T, Smith, E, Reis, Burger, Nothen, M.M Am. J. Hum. 1998; 63: 170–180Abstract Full Text PDF (108)See is, defect patients, reflected always inherited grandmother. simplest explanation this observation “epigenotype” grandmaternal epigenotype father, models how might occur hampered our lack knowledge about erasure.The control (IC), its leads syndrome, even difficult understand. As PWS, mutant wrong pattern, being largely region. 1996 identified series initiating whose would disrupted On basis, they proposed “BD exon” RNA “imprintors” switch epigenotype. This proposal seems less likely light observations does appear arise failure, occurs equally frequently mother’s grandparental chromosomes both cases 1998xSporadic 1998). consistent idea erased, then two parental equal likelihood becoming methylated. Those fail become AS, IC process unclear.While mutations instrumental localizing regulatory region, recent generation analogous found will greatly accelerate understand long-range silencing domain (Yang 1998xA imprinting-centre mutations. Yang, Adamson, T.E, Resnick, J.L, Leff, Wevrick, R, Francke, U, Jenkins, N.A, Copeland, N.G, Brannan, C.I. 19: 25–31Crossref (217)See ReferencesYang 1998).The variety mechanisms invoked explain genomic 2Figure 2) reflect fact arisen recently evolution. Mammals exploited whatever biochemical machinery available order achieve allele-specific silencing, one exception Mash2 (Caspary 1998xMultiple regulate distal 7 cluster. Caspary, Cleary, M.A, Baker, C.C, Guan, X.-J, Tilghman, S.M. Mol. Cell. Biol. 18: 3466–3474PubMedSee ReferencesCaspary 1998), every mechanism appears differential hand, apparent something fundamental regulation. X dosage compensation revealed invertebrates vertebrates, it organism commandeered different preexisting cellular goal (Lieb 1998xMIX-1 (an essential component C. elegans mitotic executes compensation) Lieb, J.D, Albrecht, M.R, Chuang, P.T, Meyer, B.J. 92: 265–277Abstract (131)See ReferencesLieb