The second major challenge is determining causality from correlation. How does one determine whether histone acetylation at the bdnf promoter causes a transcriptional or behavioral response in vivo? To address this question, one must induce or prevent histone acetylation on the bdnf gene specifically. Simply overexpressing a HAT or inhibiting HDACs would likely hyperacetylate numerous other target genes in addition to bndf, thus confounding the transcriptional and behavioral interpretations. Recently, an exciting breakthrough using zinc finger proteins may enable us to directly address this very challenging question. Zinc finger peptides can be designed or screened for highly sequence-specific DNA binding properties. These zinc finger peptides can then be fused to a chromatin remodeling enzyme, which would effectively target that enzyme to the promoter of a specific gene. This was accomplished for the first time using a DNA methyltransferase in cell culture [87, 88], and may now permit behavioral neuroscientists, using viral-mediated gene transfer, to ask whether histone modifications at specific genes are indeed causally linked to the transcriptional and behavioral phenotypes observed.
