Tet2 and H2A.Z Negatively Regulate Memory Formation in the Hippocampus

Active and dynamic DNA methylation in the hippocampus is essential for the formation, maintenance, and recall of memories (Kennedy & Sweatt, 2016); however, it does not act alone. Indeed, histone variant exchange, that is the replacement of canonical histones by histone variants, provides a novel and dynamic way in which chromatin can me modified to either restrict or promote gene transcription via the alteration of DNA-histone interactions (Zovkic et al., 2014). That said, the causative relationship between these two mechanisms has yet to be established in the hippocampus. This thesis will aim to assess the interdependence of DNA methylation and histone variant exchange by investigating alterations in methylation patterns, analyzing changes in memory-related gene expression, and exploring the effects of chromatin modifications on learning and memory. It is hypothesized that in the hippocampus, H2A.Z occupancy dictates DNA methylation via Tet enzyme regulation. In other words, the immediate eviction of H2A.Z following a learning event inhibits Tet enzyme activity which allows for the methylation of a specific region. This work implicates DNA methylation and histone variant exchange as potential therapeutic targets for memory disorders and proposes that memory is a product of the interaction between these two epigenetic marks.