Figure 6.

Strategies for epigenetic repression of risk-factor genes using Cas9 fusion proteins. Fusions containing the catalytic domain of a DNA methyltransferase cause targeted methylation of CpG sites and the recruitment of inhibitory methyl-CpG-binding proteins (i). Alternatively, a transcriptional repression domain (TRD) can be fused to Cas9, leading to the direct recruitment of transcriptional repression complexes (ii). Finally, multiple forms of inhibitory histone-modifying enzymes can be fused to Cas9, altering histone acetylation/methylation patterns and causing the formation of closed chromatin (iii).