MeCP2 regulates Tet1-catalyzed demethylation, CTCF binding, and learning-dependent alternative splicing of the BDNF gene in Turtle

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Abstract

MECP2 mutations underlying Rett syndrome cause widespread misregulation of gene expression. Functions for MeCP2 other than transcriptional are not well understood. In an ex vivo brain preparation from the pond turtle Trachemys scripta elegans, an intraexonic splicing event in the brain-derived neurotrophic factor (BDNF) gene generates a truncated mRNA transcript in naïve brain that is suppressed upon classical conditioning. MeCP2 and its partners, splicing factor Y-box binding protein 1 (YB-1) and methylcytosine dioxygenase 1 (Tet1), bind to BDNF chromatin in naïve but dissociate during conditioning; the dissociation correlating with decreased DNA methylation. Surprisingly, conditioning results in new occupancy of BDNF chromatin by DNA insulator protein CCCTC-binding factor (CTCF), which is associated with suppression of splicing in conditioning. Knockdown of MeCP2 shows it is instrumental for splicing and inhibits Tet1 and CTCF binding thereby negatively impacting DNA methylation and conditioning-dependent splicing regulation. Thus, mutations in MECP2 can have secondary effects on DNA methylation and alternative splicing.

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Zhaoqing Zheng

Neuroscience Group, Basic Biomedical Sciences, University of South Dakota, Vermillion, United States

Competing interests
The authors declare that no competing interests exist.
Ganesh Ambigapathy

Neuroscience Group, Basic Biomedical Sciences, University of South Dakota, Vermillion, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-4491-8513
Joyce Keifer

Neuroscience Group, Basic Biomedical Sciences, University of South Dakota, Vermillion, United States

For correspondence
jkeifer@usd.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-5900-0414

Funding

National Institutes of Health (NS051187)

Joyce Keifer

Internal departmental grant funds

Joyce Keifer

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All experiments involving the use of animals were performed in accordance with the guidelines of the National Institutes of Health and were approved by the USD Institutional Animal Care and Use Committee (protocol number, 08-06-14-17C).

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.