Epigenetic Editing: targeted rewriting of epigenetic marks to modulate expression of selected target genes

Abstract

Despite significant advances made in epigenetic research in recent decades, many questions remain unresolved, especially concerning cause and consequence of epigenetic marks with respect to gene expression modulation (GEM). Technologies allowing the targeting of epigenetic enzymes to predetermined DNA sequences are uniquely suited to answer such questions and could provide potent (bio)medical tools. Toward the goal of gene-specific GEM by overwriting epigenetic marks (Epigenetic Editing, EGE), instructive epigenetic marks need to be identified and their writers/erasers should then be fused to gene-specific DNA binding domains. The appropriate epigenetic mark(s) to change in order to efficiently modulate gene expression might have to be validated for any given chromatin context and should be (mitotically) stable. Various insights in such issues have been obtained by sequence-specific targeting of epigenetic enzymes, as is presented in this review. Features of such studies provide critical aspects for further improving EGE. An example of this is the direct effect of the edited mark versus the indirect effect of recruited secondary proteins by targeting epigenetic enzymes (or their domains). Proof-of-concept of expression modulation of an endogenous target gene is emerging from the few EGE studies reported. Apart from its promise in correcting disease-associated epi-mutations, EGE represents a powerful tool to address fundamental epigenetic questions.

Towards Sustained Silencing of HER2/neu in Cancer By Epigenetic Editing

“…Also, other epigenetic effector domains have been fused to ZFPs or to other types of DNA-targeting tools and were effective in gene expression modulation via their capacity for induction or reduction of their specific epigenetic marks. These effector domains include DNA methylases, histone methyltransferases, and histone acetyltransferases (27). In conclusion, the induction of epigenetic marks on a target gene using efficient rewriters of epigenetic context can result in gene expression modulation.…”

“…To induce epigenetic modifications on a target gene (epigenetic editing), catalytic domains of epigenetic enzymes can be targeted to the DNA sequences of interest. Using integrated reporter sequences, this strategy indeed resulted in gene expression modulation for several epigenetic domains (27). Modulation of expression of endogenous genes by epigenetic editing would open up exciting venues.…”

Local chromatin microenvironment determines DNMT activity: from DNA methyltransferase to DNA demethylase or DNA dehydroxymethylase

“…To identify such situations in physiological situations, the targeting of DNMTs to pre-determined genomic loci by epigenetic editing, as described by us and others previously [51][52][53][54][55] provides an interesting tool to test and to eventually exploit DNA demethylation activities of DNMTs in vivo.…”

dCas9: A Versatile Tool for Epigenome Editing

“…These DNA-binding proteins have also been used as vehicles to target epigenetic modifiers to specific loci. This application has been a major step forward in editing the epigenome (de Groote et al, 2012;Thakore et al, 2016). Below, we describe the three adaptable DNA-binding vehicles currently available for targeted recruitment of effectors at designated genomic loci.…”