The memory of learned information by the brain requires a series of biochemical reactions that ultimately result in long-term changes in gene expression within neurons and altered plasticity. Recently, epigenetic mechanisms, including active DNA demethylation, have been implicated as a source of this sustained shift in gene transcription. Here we propose a series of sequencing experiments to identify the precise genes targeted by the TET family of proteins, dioxygenases, that drive active demethylation in the CNS after learning. Then, using innovative Epi-TALE technology, we will target gene-selective changes in DNA methylation to test the hypothesis that methylation patterns at plasticity-regulated genes drive the stability of long-term memory. The proposed set of experiments have far-reaching implications for the development of new epigenetic-based therapies for diseases associated with memory loss and for disorders marked by intellectual disability.
Relevance of Research
Neuroepigenetic therapies would effect a paradigm shift for the treatment of monogenetic disorders that cause intellectual disability, such as Angelman Syndrome (Ube3a) and Pitt Hopkins Syndrome (Tcf4), both of which are characterized by one functional gene copy and one mutated copy of a plasticity-regulating gene. Additionally, neuroepigenetic therapies that target plasticity-related genes would be broadly applicable to heterogeneous diseases of memory, including Alzheimer’s disease, dementia, and mild cognitive decline.
(photo credit Josh Kuckens/Bates College)