Dnmt1 overexpression causes genomic hypermethylation, loss of imprinting, and embryonic lethality
| Autor: | Joost Gribnau, Jörn Walter, David Humpherys, Mary-Ann Mastrangelo, Detlev Biniszkiewicz, Zhan Jun, Bernard Ramsahoye, François Gaudet, Rudolf Jaenisch, Kevin Eggan |
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| Rok vydání: | 2002 |
| Předmět: |
DNA (Cytosine-5-)-Methyltransferase 1
Methyltransferase animal structures RNA Untranslated endocrine system diseases Blotting Western Gene Dosage Kruppel-Like Transcription Factors Gene Expression Biology Receptor IGF Type 2 Polyploidy Genomic Imprinting Mice Gene Order Animals DNA (Cytosine-5-)-Methyltransferases Gene Silencing RNA Messenger Imprinting (psychology) Molecular Biology Alleles In Situ Hybridization Fluorescence Regulation of gene expression Genome urogenital system Stem Cells Gene Expression Regulation Developmental Proteins Cell Biology Methylation DNA Methylation Molecular biology female genital diseases and pregnancy complications DNA methylation embryonic structures DNMT1 Embryo Loss RNA Long Noncoding Stem cell Genomic imprinting Protein Kinases Gene Deletion Transcription Factors |
| Zdroj: | Molecular and cellular biology. 22(7) |
| ISSN: | 0270-7306 |
| Popis: | Biallelic expression of Igf2 is frequently seen in cancers because Igf2 functions as a survival factor. In many tumors the activation of Igf2 expression has been correlated with de novo methylation of the imprinted region. We have compared the intrinsic susceptibilities of the imprinted region of Igf2 and H19, other imprinted genes, bulk genomic DNA, and repetitive retroviral sequences to Dnmt1 overexpression. At low Dnmt1 methyltransferase levels repetitive retroviral elements were methylated and silenced. The nonmethylated imprinted region of Igf2 and H19 was resistant to methylation at low Dnmt1 levels but became fully methylated when Dnmt1 was overexpressed from a bacterial artificial chromosome transgene. Methylation caused the activation of the silent Igf2 allele in wild-type and Dnmt1 knockout cells, leading to biallelic Igf2 expression. In contrast, the imprinted genes Igf2r, Peg3, Snrpn, and Grf1 were completely resistant to de novo methylation, even when Dnmt1 was overexpressed. Therefore, the intrinsic difference between the imprinted region of Igf2 and H19 and of other imprinted genes to postzygotic de novo methylation may be the molecular basis for the frequently observed de novo methylation and upregulation of Igf2 in neoplastic cells and tumors. Injection of Dnmt1-overexpressing embryonic stem cells in diploid or tetraploid blastocysts resulted in lethality of the embryo, which resembled embryonic lethality caused by Dnmt1 deficiency. |
| Databáze: | OpenAIRE |
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