Histone methylation at gene promoters is associated with developmental regulation and region-specific expression of ionotropic and metabotropic glutamate receptors in human brain.
Glutamatergic signaling is regulated, in part, through differential expression of NMDA and AMPA/KA channel subunits and G protein-coupled metabotropic receptors. In human brain, region-specific expression patterns of glutamate receptor genes are maintained over the course of decades, suggesting a role for molecular mechanisms involved in long-term regulation of transcription, including methylation of lysine residues at histone N-terminal tails. Using a native chromatin immunoprecipitation assay, we studied histone methylation marks at proximal promoters of 16 ionotropic and metabotropic glutamate receptor genes (GRIN1,2A-D; GRIA1,3,4; GRIK2,4,5; GRM1,3,4,6,7 ) in cerebellar cortex collected across a wide age range from midgestation to 90 years old. Levels of di- and trimethylated histone H3-lysine 4, which are associated with open chromatin and transcription, showed significant differences between promoters and a robust correlation with corresponding mRNA levels in immature and mature cerebellar cortex. In contrast, levels of trimethylated H3-lysine 27 and H4-lysine 20, two histone modifications defining silenced or condensed chromatin, did not correlate with transcription but were up-regulated overall in adult cerebellum. Furthermore, differential gene expression patterns in prefrontal and cerebellar cortex were reflected by similar differences in H3-lysine 4 methylation at promoters. Together, these findings suggest that histone lysine methylation at gene promoters is involved in developmental regulation and maintenance of region-specific expression patterns of ionotropic and metabotropic glutamate receptors. The association of a specific epigenetic mark, H3-(methyl)-lysine 4, with the molecular architecture of glutamatergic signaling in human brain has potential implications for schizophrenia and other disorders with altered glutamate receptor function.
Stadler
Florian
F
Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts Medical School, Worcester, Massachusetts 01604, USA.
Kolb
Gabriele
G
Rubusch
Lothar
L
Baker
Stephen P
SP
Jones
Edward G
EG
Akbarian
Schahram
S
D000368:Aged; D000704:Analysis of Variance; D002540:Cerebral Cortex / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D005333:Fetus; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D005865:Gestational Age; D011495:Histone-Lysine N-Methyltransferase / Q000145:classification / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D047468:Immunoprecipitation / Q000379:methods; D007231:Infant, Newborn; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D009707:Nucleosomes / Q000378:metabolism; D011180:Postmortem Changes; D011401:Promoter Regions, Genetic / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D017470:Receptors, Glutamate / Q000145:classification / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
D002843:Chromatin; D006657:Histones; D009707:Nucleosomes; D012333:RNA, Messenger; D017470:Receptors, Glutamate; D011495:Histone-Lysine N-Methyltransferase; D008239:Lysine