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 and Marianne G Rots ()
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David Cano-Rodriguez: Epigenetic Editing Research Group, University of Groningen, University Medical Centre Groningen
Rutger A F. Gjaltema: Epigenetic Editing Research Group, University of Groningen, University Medical Centre Groningen
Laura J Jilderda: Epigenetic Editing Research Group, University of Groningen, University Medical Centre Groningen
Pytrick Jellema: Epigenetic Editing Research Group, University of Groningen, University Medical Centre Groningen
Jelleke Dokter-Fokkens: Epigenetic Editing Research Group, University of Groningen, University Medical Centre Groningen
Marcel H J. Ruiters: Epigenetic Editing Research Group, University of Groningen, University Medical Centre Groningen
Marianne G Rots: Epigenetic Editing Research Group, University of Groningen, University Medical Centre Groningen

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12284

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