PT  - JOURNAL ARTICLE
AU  - C.B. Greer
AU  - J. Wright
AU  - J.D. Weiss
AU  - R.M. Lazerenko
AU  - S.P. Moran
AU  - J. Zhu
AU  - K.S. Chronister
AU  - A.Y. Jin
AU  - A.J. Kennedy
AU  - J.D. Sweatt
AU  - G.A. Kaas
TI  - <em>Tet1</em> isoforms differentially regulate gene expression, synaptic transmission and memory in the mammalian brain
AID  - 10.1101/2020.07.27.223685
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.07.27.223685
4099  - http://biorxiv.org/content/early/2020/07/29/2020.07.27.223685.1.short
4100  - http://biorxiv.org/content/early/2020/07/29/2020.07.27.223685.1.full
AB  - The dynamic regulation of DNA methylation in post-mitotic neurons is necessary for memory formation and other adaptive behaviors. Ten-eleven translocation 1 (TET1) plays a part in these processes by oxidizing 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), thereby initiating active DNA demethylation. However, attempts to pinpoint its exact role in the nervous system have been hindered by contradictory findings, perhaps due in part, to a recent discovery that two isoforms of the Tet1 gene are differentially expressed from early development into adulthood. Here, we demonstrate that both the shorter transcript (Tet1S) encoding an N-terminally truncated TET1 protein and a full-length Tet1 (Tet1FL) transcript encoding canonical TET1 are co-expressed in the adult brain. We show that Tet1S is the predominantly expressed isoform, and is highly enriched in neurons, whereas Tet1FL is generally expressed at lower levels and more abundant in glia, suggesting their roles are at least partially cell-type specific. Using viral-mediated, isoform- and neuron-specific molecular tools, we find that Tet1S repression enhances, while Tet1FL impairs, hippocampal-dependent memory. In addition, the individual disruption of the two isoforms leads to contrasting changes in basal synaptic transmission and the dysregulation of unique gene ensembles in hippocampal neurons. Together, our findings demonstrate that each Tet1 isoform serves a distinct role in the mammalian brain.Competing Interest StatementThe authors have declared no competing interest.