title: Writing of H3K4Me3 overcomes epigenetic silencing in a sustained but context-dependent manner.
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.
authors: Epigenetic Editing Research Group, Department of Pathology and Medical Biology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
authors: David
authors: D
authors: Cano-Rodriguez
authors: Epigenetic Editing Research Group, Department of Pathology and Medical Biology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
authors: Rutger A F
authors: RA
authors: Gjaltema
authors: Epigenetic Editing Research Group, Department of Pathology and Medical Biology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
authors: Laura J
authors: LJ
authors: Jilderda
authors: Epigenetic Editing Research Group, Department of Pathology and Medical Biology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
authors: Pytrick
authors: P
authors: Jellema
authors: Epigenetic Editing Research Group, Department of Pathology and Medical Biology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
authors: Jelleke
authors: J
authors: Dokter-Fokkens
authors: Epigenetic Editing Research Group, Department of Pathology and Medical Biology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
authors: Marcel H J
authors: MH
authors: Ruiters
authors: Epigenetic Editing Research Group, Department of Pathology and Medical Biology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
authors: Marianne G
authors: MG
authors: Rots
mesh_terms: D002460:Cell Line; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics*; D020868:Gene Silencing; D005818:Genetic Engineering / Q000379:methods; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism; D000072417:Protein Domains / Q000235:genetics; D015533:Transcriptional Activation
chemical_list: D002843:Chromatin; D006657:Histones; D008780:Methyltransferases