Deletion of a silencer element disrupts H19 imprinting independently of a DNA methylation epigenetic switch
| Autor: | Sheila C. Barton, M.A. Surani, Katharine L. Arney, Kathy Hilton, L. Dandolo, Justin F. X. Ainscough, Robert A. Drewell, James D. Brenton |
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| Předmět: |
DNA Replication
RNA Untranslated Gene Expression Muscle Proteins Locus (genetics) Biology Genomic Imprinting Mice Insulin-Like Growth Factor II Animals Gene Silencing Epigenetics Allele Enhancer Molecular Biology Gene Genetics Mice Inbred BALB C DNA replication DNA Methylation Mice Inbred C57BL Gene Targeting embryonic structures DNA methylation Mice Inbred CBA Female RNA Long Noncoding Genomic imprinting Gene Deletion Developmental Biology |
| Zdroj: | Europe PubMed Central |
| Popis: | The H19 imprinted gene is silenced when paternally inherited and active only when inherited maternally. This is thought to involve a cis-acting control region upstream of H19 that is responsible for regulating a number of functions including DNA methylation, asynchronous replication of parental chromosomes and an insulator. Here we report on the function of a 1.2 kb upstream element in the mouse, which was previously shown to function as a bi-directional silencer in Drosophila. The cre-loxP-mediated targeted deletion of the 1.2 kb region had no effect on the maternal allele. However, there was loss of silencing of the paternal allele in many endodermal and other tissues. The pattern of expression was very similar to the expression pattern conferred by the enhancer elements downstream of H19. We could not detect an effect on the expression of the neighbouring imprinted Igf2 gene, suggesting that the proposed boundary element insulating this gene from the downstream enhancers was unaffected. Despite derepression of the paternal H19 allele, the deletion surprisingly did not affect the differential DNA methylation of the locus, which displayed an appropriate epigenetic switch in the parental germlines. Furthermore, the characteristic asynchronous pattern of DNA replication at H19 was also not disrupted by the deletion, suggesting that the sequences that mediate this were also intact. The silencer is therefore part of a complex cis-regulatory region upstream of the H19 gene and acts specifically to ensure the repression of the paternal allele, without a predominant effect on the epigenetic switch in the germline. |
| Databáze: | OpenAIRE |
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