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Isoform-specific localization of DNMT3A regulates DNA methylation fidelity at bivalent CpG islands.
Journal article

Isoform-specific localization of DNMT3A regulates DNA methylation fidelity at bivalent CpG islands.

  • Manzo M Department of Molecular Mechanisms of Disease, University of Zurich, Zurich, Switzerland.
  • Wirz J Department of Molecular Mechanisms of Disease, University of Zurich, Zurich, Switzerland.
  • Ambrosi C Department of Molecular Mechanisms of Disease, University of Zurich, Zurich, Switzerland.
  • Villaseñor R Department of Molecular Mechanisms of Disease, University of Zurich, Zurich, Switzerland.
  • Roschitzki B Functional Genomics Center Zurich, ETH and University of Zurich, Zurich, Switzerland.
  • Baubec T Department of Molecular Mechanisms of Disease, University of Zurich, Zurich, Switzerland tuncay.baubec@uzh.ch.
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  • 2017-10-28
Published in:
  • The EMBO journal. - 2017
CpG islands
DNA methylation
DNMT3A
H3K27me3
Polycomb
Animals
Binding Sites
Cell Differentiation
Cell Line
Cells, Cultured
CpG Islands
DNA (Cytosine-5-)-Methyltransferases
DNA Methylation
Embryonic Stem Cells
Isoenzymes
Mice
Neural Stem Cells
English DNA methylation is a prevalent epigenetic modification involved in transcriptional regulation and essential for mammalian development. While the genome-wide distribution of this mark has been studied to great detail, the mechanisms responsible for its correct deposition, as well as the cause for its aberrant localization in cancers, have not been fully elucidated. Here, we have compared the activity of individual DNMT3A isoforms in mouse embryonic stem and neuronal progenitor cells and report that these isoforms differ in their genomic binding and DNA methylation activity at regulatory sites. We identify that the longer isoform DNMT3A1 preferentially localizes to the methylated shores of bivalent CpG island promoters in a tissue-specific manner. The isoform-specific targeting of DNMT3A1 coincides with elevated hydroxymethylcytosine (5-hmC) deposition, suggesting an involvement of this isoform in mediating turnover of DNA methylation at these sites. Through genetic deletion and rescue experiments, we demonstrate that this isoform-specific recruitment plays a role in de novo DNA methylation at CpG island shores, with potential implications on H3K27me3-mediated regulation of developmental genes.
Language
  • English
Open access status
hybrid
Identifiers
Persistent URL
https://sonar.ch/global/documents/74140
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