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Volumn 8, Issue 2, 1998, Pages 154-164

Imprinting mechanisms in mammals

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[No Author keywords available]

Indexed keywords

CIS ACTING ELEMENT;

EID: 0032054997     PISSN: 0959437X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0959-437X(98)80136-6     Document Type: Article
Times cited : (151)

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    • A 5′ 2-kilobase-pair region of the imprinted mouse H19 gene exhibits exclusive paternal methylation throughout development
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    • of special interest. Methylation differences between paternal and maternal chromsomes in the upstream region of H19 gene are equilibrated during early preimplantation development except for a core region of about 2 kb in which the imprint is maintained. This suggests the existence of active protective mechanisms which preserve differential methylation in imprinting core elements, whereas all other differences originating from the gametes are equilibrated.
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    • of special interest. A murine H19 transgene containing a 1.2kb portion of the upstream sequence is shown to function in cis as a parent-of-origin independent silencing element in Drosophila. Strikingly, this cis-acting element is located within an upstream region necessary for H19 imprinting in mice. The results point to evolutionary conserved mechanisms in both gene silencing in Drosophila and imprinting in mice.
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    • of special interest. Complementation of hypomethylated methyltransferase-deficient male ES cells with a Dnmt cDNA does not restore the methylation/expression patterns of imprinted genes but restores methylation in other regions. By passaging such 'rescued' ES cells through the germline in chimeric mice, however, monoallelic methylation and expression of imprinted genes is re-established. These results indicate the existence of de novo DNA methylation activities (enzymes and/or protective/enhancing factors) during gametogenesis, distinct from those observed after implantation.
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    • Aberrant methylation of an imprinted gene U2af1-rs1(SP2) caused by its own transgene
    • of special interest. The expression and methylation of the endogenous imprinted gene U2af1-rs1 can be affected by interaction with its own transgene in the testis. This suggests trans-acting mechanisms during gametogenesis which protect the U2af1-rs1 gene from methylation in the male but not in the female germline.
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    • The structural H19 gene is required for transgene imprinting
    • of special interest. The paper describes transgenic studies with the H19 gene indicating that not only sequences upstream and downstream of the structural gene but also parts in the H19 gene itself are required for both the establishment and maintenance of imprinting. Furthermore, H19 transgenic expression does not rescue the loss of Igf-2 imprinting in trans in H19 deletion mice, implying a cis requirement of the H19 gene for maintenance of Igf2 imprinting.
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    • A 5′ differentially methylated sequence and the 3′ flanking region are necessary for H19 transgene imprinting
    • of special interest. Transgenic lines were constructed containing a 14 kb genomic fragment of the H19 gene including 4 kb of 5′-flanking sequence and 8 kb of 3′-flanking sequence. The transgenes show imprinted expression which is most pronounced in high-copy-number transgenics. Deletion derivates of this transgenic construct reveal that elements in both the 5′ differentially methylated region and the 3′ region, which includes the endodermal H19 enhancers, are necessary for proper imprinting and expression of the gene.
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