Writing of H3K4Me3 overcomes epigenetic silencing in a sustained but context-dependent manner

David Cano-Rodriguez, Rutger A. F. Gjaltema, Laura J. Jilderda, Pytrick Jellema, Jelleke Dokter-Fokkens, Marcel H. J. Ruiters, Marianne G. Rots*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

99 Citations (Scopus)
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Abstract

Histone modifications reflect gene activity, but the relationship between cause and consequence of transcriptional control is heavily debated. Recent developments in rewriting local histone codes of endogenous genes elucidated instructiveness of certain marks in regulating gene expression. Maintenance of such repressive epigenome editing is controversial, while stable reactivation is still largely unexplored. Here we demonstrate sustained gene re-expression using two types of engineered DNA-binding domains fused to a H3K4 methyltransferase. Local induction of H3K4me3 is sufficient to allow re-expression of silenced target genes in various cell types. Maintenance of the re-expression is achieved, but strongly depends on the chromatin microenvironment (that is, DNA methylation status). We further identify H3K79me to be essential in allowing stable gene re-expression, confirming its role in epigenetic crosstalk for stable reactivation. Our approach uncovers potent epigenetic modifications to be directly written onto genomic loci to stably activate any given gene.

Original languageEnglish
Article number12284
Number of pages11
JournalNature Communications
Volume7
DOIs
Publication statusPublished - Aug-2016

Keywords

  • ARTIFICIAL TRANSCRIPTION FACTORS
  • DNA METHYLATION
  • HISTONE MODIFICATIONS
  • GENE-EXPRESSION
  • CHROMATIN REGULATORS
  • ENDOGENOUS GENES
  • CANCER
  • ACTIVATION
  • METHYLTRANSFERASE
  • DEMETHYLATION

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