title: Differential regulation of the phosphorylation of Trimethyl-lysine27 histone H3 at serine 28 in distinct populations of striatal projection neurons.
abstract: Phosphorylation of histone H3 (H3) on serine 28 (S28) at genomic regions marked by trimethylation of lysine 27 (H3K27me3) often correlates with increased expression of genes normally repressed by Polycomb group proteins (PcG). We show that amphetamine, an addictive psychostimulant, and haloperidol, a typical antipsychotic drug, increase the phosphorylation of H3 at S28 and that this effect occurs in the context of H3K27me3. The increases in H3K27me3S28p occur in distinct populations of projection neurons located in the striatum, the major component of the basal ganglia. Genetic inactivation of the protein phosphatase-1 inhibitor, dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), reduces the phosphorylation of H3K27me3S28 produced by amphetamine and haloperidol. In contrast, knockout of the mitogen- and stress activated kinase 1 (MSK1), which is implicated in the phosphorylation of histone H3, decreases the effect of amphetamine, but not that of haloperidol. Chromatin immunoprecipitation analysis shows that amphetamine and haloperidol increase the phosphorylation of H3K27me3S28 at the promoter regions of Atf3, Npas4 and Lipg, three genes repressed by PcG. These results identify H3K27me3S28p as a potential mediator of the effects exerted by amphetamine and haloperidol, and suggest that these drugs may act by re-activating PcG repressed target genes.
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bonito-Oliva
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Södersten
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Giada
authors.initials: G
authors.lastname: Spigolon
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Xiaochen
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Arash
authors.initials: A
authors.lastname: Hellysaz
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Falconi
authors.affiliation: Biotech Research and Innovation Centre (BRIC) and Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Ana-Luisa
authors.initials: AL
authors.lastname: Gomes
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Christian
authors.initials: C
authors.lastname: Broberger
authors.affiliation: Biotech Research and Innovation Centre (BRIC) and Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Klaus
authors.initials: K
authors.lastname: Hansen
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Gilberto
authors.initials: G
authors.lastname: Fisone
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002491:Central Nervous System Agents / Q000494:pharmacology; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000502:physiology; D006220:Haloperidol / Q000494:pharmacology; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D008049:Lipase / Q000235:genetics / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009434:Neural Pathways / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism
chemical_list: D051700:Activating Transcription Factor 3; D000661:Amphetamine; D051792:Basic Helix-Loop-Helix Proteins; D002491:Central Nervous System Agents; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D006220:Haloperidol; D006657:Histones; D008049:Lipase; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C103002:Atf3 protein, mouse; C533005:Npas4 protein, mouse; C497929:Ppp1r1b protein, mouse; C116919:mitogen and stress-activated protein kinase 1; C498741:Lipg protein, mouse
keywords: Amphetamine; Dopamine receptor; Drug action; Haloperidol; Histone modifications; Mouse; Polycomb; Protein phosphorylation; Signal transduction; Striatum