Precise alterations to the epigenome with targeted enzymes.
Since we picked genome engineering as the Method of the Year in 2011, the arrival of the CRISPR (clustered regularly interspaced short palindromic repeats) system has been hailed as a revolution for this field. The guide RNA/Cas9 nuclease complex overcomes some of the limitations of previous tools. Guide RNAs are easy to design and can target the Cas9 protein to almost any desired region in the genome. Cas9, used either as a nuclease or nickase, induces breaks in the DNA that are then exploited for gene knockout, insertion of tags or gene replacement. In fact, Cas9's potential goes beyond DNA cleavage—as a mutant without nuclease activity, it has been used to target proteins with specific functions to distinct genomic loci. It is this role of Cas9 that, in our view, is the most promising characteristic of the system and will allow its expansion from a genome-editing tool to one capable of introducing custom changes in the complex epigenome.
Two research groups recently harnessed the more established TALEs (transcription activator–like effectors) to modify the epigenome. Bernstein and colleagues targeted histone marks in enhancers with a demethylase/deacetylase complex to query their role in transcription (Nat. Biotechnol. 31, 1133–1136, 2013), and Zhang and colleagues used TALEs fused to a light-inducible system to target histone-modifying enzymes to endogenous loci and showed a repression of transcription (Nature 7463, 472–476, 2013). Although these approaches are promising, the targeting of TALEs is more cumbersome and labor intensive than targeting enzymes via the CRISPR/Cas9 system. By fusing any enzyme of choice to Cas9, one will be able to not only alter histone modification and thereby change chromatin states, but also influence DNA methylation, which would allow access to an entirely new repertoire of regulation of cellular function. Whether CRISPRs can indeed be turned into the finely honed scalpels to edit the epigenome without any concerns about off targets will become more obvious in the near future.
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Rusk, N. CRISPRs and epigenome editing. Nat Methods 11, 28 (2014). https://doi.org/10.1038/nmeth.2775
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