, 2008). Importantly, this group of modifications was observed at thousands

of gene promoters, indicating that it is a relatively general mechanism by which histone modifications may alter gene transcription (Wang et al., 2008). Although small groups of histone modifications tend to occur together, these modifications are only correlated with (rather than explicitly predictive of) increased gene expression. Moreover, exact combinations of modifications across a nucleosome are seldom repeated at different genes, indicating complex and gene-specific regulation of histone modifications. Thus, the histone code hypothesis has since been modified to consider both the context of a specific modification and the final outcome (Lee et al., 2010 and Turner, 2007), in which the histone code is considered to be the “language” that controls gene expression rather than an explicit combination of modifications beta-catenin activation that always generate an identical response.

Theoretically, the incorporation of multiple histone modifications into a code could occur in a number of ways. For Navitoclax ic50 instance, a specific modification may recruit other histone-modifying enzymes that either repress or facilitate nearby marks (Figure 1B). This appears to be the case with phosphorylation at Ser10 on H3, which both represses methylation at lysine 9 and encourages acetylation at lysine 14 (Cheung et al., 2000 and Fischle et al., 2005). Interestingly, this type of interaction may occur between different histone tails, as well as on the Oxygenase same tail (Zippo et al., 2009). Another possibility is that although certain marks may act as transcriptional repressors under some cases, they may facilitate transcription in the presence

of another mark on the same histone tail. This would explain why a number of histone modifications have been associated with both transcriptional activation and transcriptional repression and why sets of marks that are both independently correlated with transcriptional activation do not necessarily always occur together (Barski et al., 2007). Yet another means by which specific histone modifications could combine to produce a unique epigenetic signature is via the inherent kinetics underlying each reaction. Histone acetylation and phosphorylation are likely reversed very rapidly, whereas histone methylation may persist for longer periods of time. This would allow these mechanisms to synergistically control gene expression across unique time courses despite having no direct interactions. Overwhelming evidence indicates that histone modifications in the CNS are essential components of memory formation and consolidation. Indeed, multiple types of behavioral experiences are capable of inducing histone modifications in several brain regions (Bredy et al., 2007, Chwang et al., 2007, Fischer et al., 2007, Gupta et al.