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PMID: 14749379 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Dnmt1 expression in pre- and postimplantation embryogenesis and the maintenance of IAP silencing.

Molecular and cellular biology ·Vol. 24 ·No. 4 ·2004-02-00 ·Pages 1640-8

Gaudet F, Rideout WM, Meissner A, Dausman J, Leonhardt H, Jaenisch R

Abstract

The methylation of intracisternal A-type particle (IAP) sequences is maintained during mouse embryogenesis. Methylation suppresses IAP expression and the potential for mutagenesis by retrotransposition, but it is not clear how methylation of these elements is maintained during the embryonic stages when the bulk of the genome is being demethylated. It has been suggested that the high levels of DNA methyltransferase-1 (Dnmt1) present during cleavage could be important for keeping IAPs methylated. To test this hypothesis, we combined mutant alleles of Dnmt1 with an agouti allele (A(iapy)), which provided a coat color readout for the methylation status of the IAP insertion in the agouti locus. We found that reduction in Dnmt1 levels directly impacted methylation at this locus, leading to stable transcriptional activation of the agouti gene in the adult. Specifically, the short maternal Dnmt1 protein was important in maintaining methylation at the A(iapy) locus in cleavage embryos, whereas the longer Dnmt1 isoform found in somatic cells was important in maintaining IAP methylation during the postimplantation stage. These results underscore the importance of maintaining proper maintenance of methylation patterns during gestation and suggest that interference with this process may stably affect gene expression patterns in the adult and may have profound phenotypic consequences.

MeSH Terms
Agouti Signaling Protein Alleles Animals DNA (Cytosine-5-)-Methyltransferase 1 DNA (Cytosine-5-)-Methyltransferases/genetics,metabolism DNA Methylation Embryo, Mammalian/embryology,metabolism Embryonic Development Female Gene Expression Regulation, Developmental Gene Silencing Genes, Intracisternal A-Particle/genetics Genotype Hair Color/genetics Intercellular Signaling Peptides and Proteins/genetics Mice Phenotype Pregnancy
Chemicals
Agouti Signaling Protein Intercellular Signaling Peptides and Proteins DNA (Cytosine-5-)-Methyltransferase 1 DNA (Cytosine-5-)-Methyltransferases Dnmt1 protein, mouse
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Gaudet F
Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
Rideout W M
Meissner A
Dausman J
Leonhardt H
Jaenisch R
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.24.4.1640-1648.2004
Published
2004-02-00
Pages
1640-8
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC344181
Subset
IM
Grants
NCI NIH HHS · R01 CA087869 · United States
NCI NIH HHS · 5-R01-CA87869 · United States
External Links
PubMed source DOI: 10.1128/MCB.24.4.1640-1648.2004 PMC Full Text View journal details
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