Protein phosphatase 1 regulates the histone code for long-term memory.
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.
Koshibu
Kyoko
K
Brain Research Institute, University of Zürich, Swiss Federal Institute of Technology, CH-8057 Zurich, Switzerland.
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
D000704:Analysis of Variance; D000818:Animals; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly / Q000502:physiology; D047369:Chromatin Immunoprecipitation / Q000379:methods; D004193:Discrimination Learning / Q000502:physiology; D004318:Doxycycline / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000166:cytology / Q000502:physiology; D042421:Histone Code / Q000502:physiology*; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D066298:In Vitro Techniques; D008568:Memory / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000648:ultrastructure; D009483:Neuropsychological Tests; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D016548:Prosencephalon / Q000166:cytology / Q000378:metabolism; D054645:Protein Phosphatase 1 / Q000235:genetics / Q000502:physiology*; D014161:Transduction, Genetic / Q000379:methods
D006657:Histones; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D010089:Oxidoreductases, N-Demethylating; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D054645:Protein Phosphatase 1; D006655:Histone Deacetylases; D004318:Doxycycline