Direct interaction between DNMT1 and G9a coordinates DNA and histone methylation during replication

Pierre Olivier Estève, Gyeong Chin Hang, Andrea Smallwood, George R. Feehery, Omkaram Gangisetty, Adam R. Karpf, Michael F. Carey, Sriharsa Pradhan

Research output: Contribution to journalArticle

353 Scopus citations

Abstract

Chromatin methylation is necessary for stable repression of gene expression during mammalian development. During cell division, DNMT1 maintains the DNA methylation pattern of the newly synthesized daughter strand, while G9a methylates H3K9. Here, DNMT1 is shown to directly bind G9a both in vivo and in vitro and to colocalize in the nucleus during DNA replication. The complex of DNMT1 and G9a colocalizes with dimethylated H3K9 (H3K9me2) at replication foci. Similarly, another H3K9 histone methyltransferase, SUV39H1, colocalizes with DNMT1 on heterochromatic regions of the nucleoli exclusively before cell division. Both DNMT1 and G9a are loaded onto the chromatin simultaneously in a ternary complex with loading factor PCNA during chromatin replication. Small interfering RNA (siRNA) knockdown of DNMT1 impairs DNA methylation, G9a loading, and H3K9 methylation on chromatin and rDNA repeats, confirming DNMT1 as the primary loading factor. Additionally, the complex of DNMT1 and G9a led to enhanced DNA and histone methylation of in vitro assembled chromatin substrates. Thus, direct cooperation between DNMT1 and G9a provides a mechanism of coordinated DNA and H3K9 methylation during cell division.

Original languageEnglish (US)
Pages (from-to)3089-3103
Number of pages15
JournalGenes and Development
Volume20
Issue number22
DOIs
StatePublished - Nov 15 2006

Keywords

  • Chromatin
  • DNMT1
  • G9a
  • Methylation
  • Replication
  • SUV39H1

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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    Estève, P. O., Hang, G. C., Smallwood, A., Feehery, G. R., Gangisetty, O., Karpf, A. R., Carey, M. F., & Pradhan, S. (2006). Direct interaction between DNMT1 and G9a coordinates DNA and histone methylation during replication. Genes and Development, 20(22), 3089-3103. https://doi.org/10.1101/gad.1463706