Loss of neuronal Tet2 enhances hippocampal-dependent cognitive function

Karishma J B Pratt; Jeremy M Shea; Laura Remesal-Gomez; Gregor Bieri; Lucas K Smith; Julien Couthouis; Christopher P Chen; Irena J Roy; Geraldine Gontier; Saul A Villeda

doi:10.1016/j.celrep.2022.111612

Loss of neuronal Tet2 enhances hippocampal-dependent cognitive function

Cell Rep. 2022 Nov 8;41(6):111612. doi: 10.1016/j.celrep.2022.111612.

Authors

Affiliations

¹ Department of Anatomy, University of California San Francisco, 513 Parnassus Avenue, Box 0452, San Francisco, CA 94143, USA; Developmental and Stem Cell Biology Graduate Program, University of California San Francisco, San Francisco, CA 94143, USA.
² Department of Anatomy, University of California San Francisco, 513 Parnassus Avenue, Box 0452, San Francisco, CA 94143, USA.
³ Department of Anatomy, University of California San Francisco, 513 Parnassus Avenue, Box 0452, San Francisco, CA 94143, USA; Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, CA 94143, USA.
⁴ Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁵ Developmental and Stem Cell Biology Graduate Program, University of California San Francisco, San Francisco, CA 94143, USA.
⁶ Department of Anatomy, University of California San Francisco, 513 Parnassus Avenue, Box 0452, San Francisco, CA 94143, USA. Electronic address: gontier.geraldine@gmail.com.
⁷ Department of Anatomy, University of California San Francisco, 513 Parnassus Avenue, Box 0452, San Francisco, CA 94143, USA; Developmental and Stem Cell Biology Graduate Program, University of California San Francisco, San Francisco, CA 94143, USA; Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, CA 94143, USA; Department of Physical Therapy and Rehabilitation Science, San Francisco, CA 94143, USA; Bakar Aging Research Institute, San Francisco, CA 94143, USA. Electronic address: saul.villeda@ucsf.edu.

Abstract

DNA methylation has emerged as a critical modulator of neuronal plasticity and cognitive function. Notwithstanding, the role of enzymes that demethylate DNA remain to be fully explored. Here, we report that loss of ten-eleven translocation methylcytosine dioxygenase 2 (Tet2), which catalyzes oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), in adult neurons enhances cognitive function. In the adult mouse hippocampus, we detected an enrichment of Tet2 in neurons. Viral-mediated neuronal overexpression and RNA interference of Tet2 altered dendritic complexity and synaptic-plasticity-related gene expression in vitro. Overexpression of neuronal Tet2 in adult hippocampus, and loss of Tet2 in adult glutamatergic neurons, resulted in differential hydroxymethylation associated with genes involved in synaptic transmission. Functionally, overexpression of neuronal Tet2 impaired hippocampal-dependent memory, while loss of neuronal Tet2 enhanced memory. Ultimately, these data identify neuronal Tet2 as a molecular target to boost cognitive function.

Keywords: CP: Molecular biology; CP: Neuroscience; TET2; chromatin; cognition; epigenetics; hippocampus; hydroxymethylation; memory; methylation; neurons.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

5-Methylcytosine / metabolism
Animals
Cognition
DNA Methylation / genetics
DNA-Binding Proteins / metabolism
Dioxygenases* / genetics
Hippocampus / metabolism
Mice
Neurons / metabolism
Proto-Oncogene Proteins* / genetics
Proto-Oncogene Proteins* / metabolism

Substances

Proto-Oncogene Proteins
DNA-Binding Proteins
5-Methylcytosine
Dioxygenases
Tet2 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding