title: Repressive epigenetic changes at the mGlu2 promoter in frontal cortex of 5-HT2A knockout mice.
abstract: Serotonin 5-HT(2A) and metabotropic glutamate 2 (mGlu2) are G protein-coupled receptors suspected in the pathophysiology of psychiatric disorders, such as schizophrenia, depression, and suicide. Previous findings demonstrate that mGlu2 mRNA expression is down-regulated in brain cortical regions of 5-HT2A knockout (KO) mice. However, the molecular mechanism responsible for this alteration remains unknown. We show here repressive epigenetic changes at the promoter region of the mGlu2 gene in frontal cortex of 5-HT(2A)-KO mice. Disruption of 5-HT(2A) receptor-dependent signaling in mice was associated with decreased acetylation of histone H3 (H3ac) and H4 (H4ac) and increased tri-methylation of histone H3 at lysine 27 (H3K27me3) at the mGlu2 promoter, epigenetic changes that correlate with transcriptional repression. Neither methylation of histone H3 at lysine 4 (H3K4me1/2/3) nor tri-methylation of histone H3 at lysine 9 (H3K9me3) was affected. We found that Egr1, a transcription factor in which promoter activity was positively regulated by the 5-HT(2A) receptor agonist 4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine hydrobromide, binds less to the mGlu2 promoter in frontal cortex of 5-HT(2A)-KO, compared with wild-type mice. Furthermore, expression of mGlu2 was increased by viral-mediated gene transfer of FLAG-tagged Egr1 in mouse frontal cortex. Together, these observations suggest that 5-HT(2A) receptor-dependent signaling epigenetically affects mGlu2 transcription in mouse frontal cortex.
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Mitsumasa
authors.initials: M
authors.lastname: Kurita
authors.forename: José L
authors.initials: JL
authors.lastname: Moreno
authors.forename: Terrell
authors.initials: T
authors.lastname: Holloway
authors.forename: Alexey
authors.initials: A
authors.lastname: Kozlenkov
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Mocci
authors.forename: Aintzane
authors.initials: A
authors.lastname: García-Bea
authors.forename: James B
authors.initials: JB
authors.lastname: Hanks
authors.forename: Rachael
authors.initials: R
authors.lastname: Neve
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Russo
authors.forename: Javier
authors.initials: J
authors.lastname: González-Maeso
mesh_terms: D000818:Animals; D019175:DNA Methylation; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D005625:Frontal Lobe / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics*; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics* / Q000378:metabolism
chemical_list: D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D006657:Histones; D044402:Receptor, Serotonin, 5-HT2A; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2