Genome-wide investigation of the dynamic changes of epigenome modifications after global DNA methylation editing

Nucleic Acids Res. 2021 Jan 11;49(1):158-176. doi: 10.1093/nar/gkaa1169.

Abstract

Chromatin properties are regulated by complex networks of epigenome modifications. Currently, it is unclear how these modifications interact and if they control downstream effects such as gene expression. We employed promiscuous chromatin binding of a zinc finger fused catalytic domain of DNMT3A to introduce DNA methylation in HEK293 cells at many CpG islands (CGIs) and systematically investigated the dynamics of the introduced DNA methylation and the consequent changes of the epigenome network. We observed efficient methylation at thousands of CGIs, but it was unstable at about 90% of them, highlighting the power of genome-wide molecular processes that protect CGIs against DNA methylation. Partially stable methylation was observed at about 1000 CGIs, which showed enrichment in H3K27me3. Globally, the introduced DNA methylation strongly correlated with a decrease in gene expression indicating a direct effect. Similarly, global but transient reductions in H3K4me3 and H3K27ac were observed after DNA methylation but no changes were found for H3K9me3 and H3K36me3. Our data provide a global and time-resolved view on the network of epigenome modifications, their connections with DNA methylation and the responses triggered by artificial DNA methylation revealing a direct repressive effect of DNA methylation in CGIs on H3K4me3, histone acetylation, and gene expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Catalytic Domain / genetics
  • Chromatin / chemistry
  • Chromatin / genetics
  • Chromatin / metabolism
  • Chromatin Immunoprecipitation
  • CpG Islands / genetics*
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • DNA (Cytosine-5-)-Methyltransferases / metabolism*
  • DNA Methylation*
  • DNA Methyltransferase 3A
  • Gene Editing*
  • Gene Expression Regulation / genetics*
  • Genome
  • HEK293 Cells
  • Histone Code*
  • Humans
  • Lysine / chemistry
  • Protein Binding
  • Protein Processing, Post-Translational
  • Recombinant Fusion Proteins / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Analysis, RNA
  • Zinc Fingers / genetics

Substances

  • Chromatin
  • DNMT3A protein, human
  • Recombinant Fusion Proteins
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA Methyltransferase 3A
  • Lysine