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The Journal of Neuroscience, October 14, 2009, 29(41):13079-13089; doi:10.1523/JNEUROSCI.3610-09.2009

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Behavioral/Systems/Cognitive
Protein Phosphatase 1 Regulates the Histone Code for Long-Term Memory

Kyoko Koshibu,^1 * Johannes Gräff,^1 * Monique Beullens,³ Fabrice D. Heitz,¹ Dominik Berchtold,^1,2 Holger Russig,¹ Mélissa Farinelli,¹ Mathieu Bollen,³ and Isabelle M. Mansuy¹

¹Brain Research Institute, Medical Faculty of the University of Zürich and Department of Biology of the Swiss Federal Institute of Technology, and ²Institute for Human Movement Sciences and Sport, Department of Biology of the Swiss Federal Institute of Technology, CH-8057 Zurich, Switzerland, and ³Laboratory of Biosignaling and Therapeutics, Department of Molecular Cell Biology, University of Leuven, B-3000 Leuven, Belgium

Correspondence should be addressed to Isabelle M. Mansuy at the above address. Email: mansuy{at}hifo.uzh.ch

Chromatin remodeling through histone posttranslational modifications (PTMs) and DNA methylation has recently been implicated in cognitive functions, but the mechanisms involved in such epigenetic regulation remain poorly understood. Here, we show that protein phosphatase 1 (PP1) is a critical regulator of chromatin remodeling in the mammalian brain that controls histone PTMs and gene transcription associated with long-term memory. Our data show that PP1 is present at the chromatin in brain cells and interacts with enzymes of the epigenetic machinery including HDAC1 (histone deacetylase 1) and histone demethylase JMJD2A (jumonji domain-containing protein 2A). The selective inhibition of the nuclear pool of PP1 in forebrain neurons in transgenic mice is shown to induce several histone PTMs that include not only phosphorylation but also acetylation and methylation. These PTMs are residue-specific and occur at the promoter of genes important for memory formation like CREB (cAMP response element-binding protein) and NF-B (nuclear factor-B). These histone PTMs further co-occur with selective binding of RNA polymerase II and altered gene transcription, and are associated with improved long-term memory for objects and space. Together, these findings reveal a novel mechanism for the epigenetic control of gene transcription and long-term memory in the adult brain that depends on PP1.

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Received July 26, 2009; revised Sept. 1, 2009; accepted Sept. 4, 2009.

Correspondence should be addressed to Isabelle M. Mansuy at the above address. Email: mansuy{at}hifo.uzh.ch

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