Origins of extreme sexual dimorphism in genomic imprinting.
Roughly equal numbers of imprinted genes are subject to repression from alleles of maternal and of paternal origin. This masks the strong sexual dimorphism that underlies major aspects of imprinted gene regulation. First, imprints are established very early in the male germ line and persist for the reproductive life of the organism, while maternal genomic imprints are established shortly prior to ovulation and are erased soon thereafter in the primordial germ cells of the next generation. Second, many CpG island-associated promoters are subject to maternal methylation but no known promoters are subject to paternal-specific germline methylation. The few known paternal methylation marks are kilobases distant from the affected genes and have a low CpG density. Third, Dnmt3L is required for imprint establishment but not transposon methylation in female germ cells, while Dnmt3L is required for transposon methylation and has only a minor role in de novo methylation at imprinted loci in male germ cells. Fourth, maternally expressed genes are commonly repressed on the paternal allele by paternally expressed imprinted genes produced in cis and encoding nontranslated RNAs. It is here suggested that rapid loss of highly mutable methylated CpG sites has led to the depletion of methylation target sites in paternally repressed imprinted genes, and that an imprinting mechanism based on RNAs or local inhibitory influences of ongoing transcription of regulatory loci has evolved to counter the erosion of paternally methylated regulatory regions. This mutability model is based on the fact that paternally methylated sequences are maintained in the methylated state for a much longer time than are maternally methylated sequences, and are therefore lost at a correspondingly faster rate. The difference in timing of imprint establishment is likely to underlie the increasing sexual dimorphism of other aspects of imprinted gene expression.
Bourc'his
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Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Bestor
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D000818:Animals; D019175:DNA Methylation; D005260:Female; D018392:Genomic Imprinting; D008297:Male; D008957:Models, Genetic; D009154:Mutation; D012727:Sex Characteristics