Optoepigenetics. As discussed above, the epigenetic toolbox would also ideally include a method
that enables manipulations with some degree of temporal precision. Although this goal remains in
an experimentally embryonic stage, it is worth noting that recent advances show much promise.
Perhaps the greatest advance comes from the combination of optogenetic tools with the TALE
systems described above (93). This approach uses cryptochrome 2 (CRY2), a light-sensitive protein
from Arabidopsis thaliana, which exhibits a conformational change and binds to a partner protein
[cryptochrome-interacting basic-helix-loop-helix 1 (CIB1)] in the presence of blue light. Thus, by
fusing an effector protein such as a DNMT to CIB1 and CRY2 directly to a site-specific TALE
domain, this system could be used as a light-guided switch to generate methylation of DNA
with complete temporal control (Figure 3). This approach has already been employed to target
generic transcriptional activators and repressive histone modifying enzymes to DNA (93) and is
characterized by a very rapid response time (>1 h) that overlaps with the temporal dynamics of
cognitive phenomena. This general technique could capitalize on growing optogenetic resources,
allowing for a full set of optoepigenetic tools to manipulate DNA methylation in discrete brain
regions using implanted fiber optic cables.