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Author Notes:

To whom correspondence should be addressed: eric.nestler@mssm.edu

The studies were conceived and designed by E.J.N., P.J., and J.F.

J.F. performed RNA-seq and ChIP-seq.

K.E.S., Y.L., and J.F. performed 5hmC capture and sequencing.

L.S., N.S., and J.F. performed bioinformatic analyses.

J.F. and J.H. performed oxBS-seq.

J.F., V.V., B.M.L., V.S., and I.M. performed qPCR analyses.

V.V., D.E., T.C., and J.F. performed immunohistochemistry.

J.F., V.V., D.F., J.K., and E.R. performed stereotaxic surgeries and behavioral assays.

T.L., K.F.F., and G.F. contributed LC-ESI-MS/MS data.

C.Z. and H.S. provided AAV-Tet1shRNA and AAV-TET1 viruses.

M.E.C. performed Western blotting.

G.T. contributed human samples.

D.F., B.L., B.M.L., V.S., and P.K. also helped to prepare the samples and collect the data.

The paper was written by J.F. and E.J.N. and was edited by other authors.

We thank A. Chess for critical comments, and O. Jabado and M. Mahajan from the Mount Sinai Genomics Core for technical support.

The authors declare no competing financial interests.

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Research Funding:

This work was supported by grants from the National Institute on Drug Abuse (E.J.N.) and National Institutes of Health (P.J., P.C., G.F., H.S.).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Neurosciences & Neurology
  • DNA DEMETHYLATION
  • NUCLEUS-ACCUMBENS
  • GENE-EXPRESSION
  • DELTA-FOSB
  • MEMORY FORMATION
  • DRUG-ADDICTION
  • MAMMALIAN DNA
  • 5-METHYLCYTOSINE
  • TRANSCRIPTION
  • ENHANCERS

Role of Tet1 and 5-hydroxymethylcytosine in cocaine action

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Journal Title:

Nature Neuroscience

Volume:

Volume 18, Number 4

Publisher:

, Pages 536-+

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Ten-eleven translocation (TET) enzymes mediate the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), which is enriched in brain, and its ultimate DNA demethylation. However, the influence of TET and 5hmC on gene transcription in brain remains elusive. We found that ten-eleven translocation protein 1 (TET1) was downregulated in mouse nucleus accumbens (NAc), a key brain reward structure, by repeated cocaine administration, which enhanced behavioral responses to cocaine. We then identified 5hmC induction in putative enhancers and coding regions of genes that have pivotal roles in drug addiction. Such induction of 5hmC, which occurred similarly following TET1 knockdown alone, correlated with increased expression of these genes as well as with their alternative splicing in response to cocaine administration. In addition, 5hmC alterations at certain loci persisted for at least 1 month after cocaine exposure. Together, these reveal a previously unknown epigenetic mechanism of cocaine action and provide new insight into how 5hmC regulates transcription in brain in vivo.

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© 2015 Nature America, Inc. All rights reserved.

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