Imprinting of the mouse Igf2r gene depends on an intronic CpG island
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文摘
Gametic imprinting is a developmental process that uses cis-acting epigenetic mechanisms to induce parental-specific expression in autosomal and X-linked genes. From the limited knowledge we have of imprinted genes it seems clear that they play a role in regulating the growth and development of the placenta and embryo in utero, and also in the early post-natal phase. The biological function of imprinting in mammals is not yet understood but it may act to regulate the supply of nutrition to the embryo in order to maintain a balance between fetal demands and maternal resources. The molecular basis of imprinting any gene has not yet been disclosed. However, the current model proposes that single or clustered genes should be associated with a specific imprinting element which carries a reversible epigenetic imprinting signal, inherited from one parent and maintained on the same parental chromosome in diploid cells. A common imprinting recognition sequence has not been identified amongst the 20 known imprinted genes, but such an element is thought to exist from observations of mouse transgenes and transgenes of the imprinted H19 gene, which have shown that short DNA sequences can maintain imprinted expression at different chromosome locations. However, it is also clear from gene deletion experiments in the mouse and the analysis of deletions in the human Prader-Willi/Angelman syndromes that imprinted genes are also influenced by distant DNA sequences. We have earlier proposed that CG rich sequences resembling CpG islands, which are associated with many imprinted genes and often subject to parental-specific methylation, could act as a common imprinting element. The mouse insulin-like growth factor type 2 receptor (Igf2r) gene contains a CpG island known as region2, in the second intron. Region2 was proposed as the imprinting element of this gene because it inherited a methylation imprint from the female gamete that was maintained only on the maternal chromosome in diploid cells. We have used YAC (yeast artificial chromosome) transgenes carrying the complete Igf2r locus, to test if imprinting and parental-specific methylation of the mouse Igf2r gene is maintained when transferred to other chromosomal locations and to test whether imprinting is dependent on the intronic CpG island proposed as the imprinting element for this gene. Gametic imprints are epigenetic modifications which are imposed onto the gametic chromosomes and cause parental-specific differences in the expression of a small number of genes in the embryo. As a consequence, correct imposition of the imprints in the parental germlines is a prerequisite for successful development of mammals and any anomaly in the expression of imprinted genes is often accompanied by aberration of embryonic growth. The link between imprinting and growth regulation is best exemplified by the Igf2 and Igf2r genes. Both genes show parental-specific expression patterns in the embryo. Igf2 is a general embryonic mitogen, and mice lacking Igf2 are markedly reduced in size (DeChiara, T.M., Robertson, E.J., Efstratiadis, A., 1991. Parental imprinting of the mouse insulin-like growth factor II gene. Cell 64, 849–859). Igf2r acts to fine tune the amount of growth factor, and embryos lacking this gene show overgrowth and die perinatally (Lau, M.M., Stewart, C.E., Liu, Z., Bhatt, H., Rotwein, P., Stewart, C.L., 1994. Loss of the imprinted IGF2/cation-independent mannose 6-phosphate receptor results in fetal overgrowth and perinatal lethality. Genes Dev. 8, 2953–2963; Wang, Z.Q., Fung, M.R., Barlow, D.P., Wagner, E.F., 1994. Regulation of embryonic growth and lysosomal targeting by the imprinted Igf2/Mpr gene. Nature 372, 464–467). The phenomenon of gametic imprinting is predicted to arise by an unusual regulation of the imposition and erasure of epigenetic modifications. There are three events which are required for imprinting: firstly, the imprint must be imposed in one of the gametes before fertilisation. Secondly, the difference between the parental chromosomes must be maintained in early development despite the fact that the embryonic genome becomes epigenetically reprogrammed. Thirdly, the imprint must be erased in the germline before a new one is established (failure to erase the imprint would lead to a stably inherited epigenetic state over the generations). The focus of this review is the imprinted mouse Igf2r gene. The present understanding of the mechnism imprinting this locus is summarized, compared with other imprinted genes, and a model to explain the data is discussed.