Protein phosphatase 1 regulates the histone code for long-term memory.

Full Abstract

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-kappaB (nuclear factor-kappaB). 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.

Author information

Author/s: Koshibu, Kyoko (K); Gräff, Johannes (J); Beullens, Monique (M); Heitz, Fabrice D (FD); Berchtold, Dominik (D); Russig, Holger (H); Farinelli, Mélissa (M); Bollen, Mathieu (M); Mansuy, Isabelle M (IM);

Affiliation: Brain Research Institute, University of Zürich, Swiss Federal Institute of Technology, CH-8057 Zurich, Switzerland.

Journal and publication information

Publication Type: In Vitro; Journal Article; Research Support, Non-U.S. Gov't

Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci), published in United States. (Language: eng)

Reference: 2009-Oct; vol 29 (issue 41) : pp 13079-89

Dates: Created 2009/10/15; Completed 2009/10/30;

PMID: 19828821, status: MEDLINE (last retrieval date: 10/30/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Histone Code - physiology
Histone Deacetylases - metabolism
Histones - metabolism
Memory - physiology
Mice
Mice, Transgenic
Neurons - ultrastructure
Neuropsychological Tests
Oxidoreductases, N-Demethylating - metabolism
Prosencephalon - cytology; metabolism
Protein Phosphatase 1 - genetics; physiology
Transduction, Genetic - methods

Associated Chemicals: Histones (0) ; enhanced green fluorescent protein (0) ; Green Fluorescent Proteins (147336-22-9) ; Doxycycline (564-25-0) ; Oxidoreductases, N-Demethylating (EC 1.5.-) ; Calcium-Calmodulin-Dependent Protein Kinase Kinase (EC 2.7.11.17) ; Protein Phosphatase 1 (EC 3.1.3.16) ; Histone Deacetylases (EC 3.5.1.-)

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