The role of TET1-mediated demethylation in gene regulation and memory formation. A. J. Towers1, XL. Li2, A. L. Bey3, P. Wang2, YH. Jiang1,2,3 1) Program in Genetics and Genomics, Duke University, Durham, NC; 2) Pediatrics Dept, Duke University, Durham, NC; 3) Neurobiology Dept, Duke University, Durham, NC.
Dynamic regulation of gene expression is implicated in memory formation, although the molecular mechanism remains poorly understood. Accumulating evidence suggests epigenetic modifications are part of the mechanism. Activity-induced DNA demethylation occurs in the hippocampus after learning or electrical stimulation, but the enzymes responsible for it have been elusive. Recently, the oxygenases of the Ten-eleven translocation (TET) family, including TET1, were suggested to play a role in DNA demethylation in the postnatal brain, particularly the hippocampus, a region important for memory formation. The function of TET1 and 5hmC in the postnatal brain, however, is unclear. We hypothesized that TET1 plays an important role in memory formation by regulating activity-dependent gene expression via DNA demethylation.
We have successfully obtained Tet1 exon3 deletion mice. To determine if activity-dependent genes are dysregulated in Tet1-/- hippocampi after stimulation, we performed electroconvulsive shock in Tet1-/- and Tet1+/+ mice and compared the expression profile by RNA-seq. We used TopHat to align reads and Cufflinks to find differentially expressed genes. The expression of a master, memory gene regulator, Npas4, was significantly downregulated in Tet1-/- samples. We then used bisulfite sequencing to examine the promoter region of Npas4 and found it to have increased DNA methylation in Tet1-/- samples, suggesting a role for TET1 in regulating the methylation state of Npas4. Gene Ontology analyses of the dysregulated genes using DAVID revealed a significant enrichment for genes involved in the extracellular matrix (ECM), a structure which has been implicated in synaptic plasticity.
We then performed a battery of behavioral tests to address whether hippocampus-dependent learning and memory formation are affected in Tet1-/- mice. We discovered both short-term (1 hr) and long-term (24 hr) episodic memory deficits in Tet1-/- mice in the novel object recognition and the social transmission of food preference behavioral paradigms.
Our study suggests a role for TET1 in regulating gene expression important for memory formation. A better understanding of the molecular mechanisms of memory formation will be critical for finding future therapies for human memory disorders.
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