The Past, Presence and Future of Targeting Epigenetic Marks: From Chemicals and DNA Via Proteins to RNA and Clinical Gene Therapy

The ability to target DNA specifically at any given position within the genome allows many intriguing possibilities and has inspired scientists for decades. Early gene targeting approaches exploited chemicals or DNA oligonucleotides to interfere with the DNA at a given locus in order to inactivate a gene or correct mutations. In addition to the promise of gene correction, scientists soon realized that genes could be silenced and even re-activated without inducing potentially harmful DNA damage, by targeting transcriptional modulators to a particular gene.¹ These first generation programmable DNA binding domains (polyamides, triplex forming oligonucleotides), however, proved difficult to fuse protein effector domains to.² The engineering of gene-targeting proteins (ZFPs, TALEs) circumvented this problem, but required new protein fusions for each locus. The more recent introduction of CRISPR/Cas offers a flexible approach to target fusion dCas-proteins to the locus of interest using cheap designer RNA molecules. Many research groups now exploit this platform and the first human clinical trials have been initiated: CRISPR/Cas has kicked off a new era of gene targeting and is revolutionizing biomedical sciences.

Following the increasing awareness of frequent epigenetic dysregulations in human diseases, and the success of clinically approved epigenetic drugs, the gene targeting platforms have been repurposed to edit epigenetic signatures at any given locus.³ Currently, this approach has convincingly demonstrated causality of various epigenetic modifications in instructing gene expression and has provided exciting indications supporting the promise to interfere with disease-associated gene expression dysregulations. Some reports indicate the feasibility of long-term gene repression as well as re-expression,³ but solid guidelines on how to stably interfere with epigenetic gene regulation in any given chromatin environment are largely lacking. The expected progress in this aspect, together with developments in safe delivery methods, open novel therapeutic avenues and editing epigenetic signatures might realize the “curable epigenome” concept for currently untreatable diseases.

¹ Uil TG, Haisma HJ, Rots MG. Therapeutic modulation of endogenous gene function by agents with designed DNA-sequence specificities. Nucleic Acids Res. 2003

² Geel TM, Ruiters MHJ, …, Arimondo PB, Rots MG. The past and presence of DNA targeting: from chemicals and DNA via proteins to RNA. Philos Trans R Soc Lond B Biol Sci (in press)

³ De Groote ML, Verschure PJ, Rots MG. Epigenetic Editing: Targeted Rewriting of Epigenetic Marks to Modulate Expression of Selected Target Genes. Nucleic Acids Res. 2012

⁴ Cano-Rodriguez D, Gjaltema RAF, Jilderda LJ, Jellema P, Dokter-Fokkens J, Ruiters MHJ, Rots MG. Writing of H3K4Me3 overcomes epigenetic silencing in a sustained, but context-dependent manner. Nat Commun. 2016

Financial support includes an EU SNN grant and an H2020 ITN grant (www.EpiPredict.eu). Networking activities are supported by EU COST CM1406 (www.EpiChemBio.eu).