title: The histone lysine demethylase Kdm6b is required for activity-dependent preconditioning of hippocampal neuronal survival.
abstract: Enzymes that regulate histone lysine methylation play important roles in neuronal differentiation, but little is known about their contributions to activity-regulated gene transcription in differentiated neurons. We characterized activity-regulated expression of lysine demethylases and lysine methyltransferases in the hippocampus of adult male mice following pilocarpine-induced seizure. Pilocarpine drove a 20-fold increase in mRNA encoding the histone H3 lysine 27-specific demethylase Kdm6b selectively in granule neurons of the dentate gyrus, and this induction was recapitulated in cultured hippocampal neurons by bicuculline and 4-aminopyridine (Bic + 4AP) stimulation of synaptic activity. Because activity-regulated gene expression is highly correlated with neuronal survival, we tested the requirement for Kdm6b expression in Bic + 4AP induced preconditioning of neuronal survival. Prior exposure to Bic + 4AP promoted neuronal survival in control neurons upon growth factor withdrawal; however, this effect was ablated when we knocked down Kdm6b expression. Loss of Kdm6b did not disrupt activity-induced expression of most genes, including that of a gene set previously established to promote neuronal survival in this assay. However, using bioinformatic analysis of RNA sequencing data, we discovered that Kdm6b knockdown neurons showed impaired inducibility of a discrete set of genes annotated for their function in inflammation. These data reveal a novel function for Kdm6b in activity-regulated neuronal survival, and they suggest that activity- and Kdm6b-dependent regulation of inflammatory gene pathways may serve as an adaptive pro-survival response to increased neuronal activity.
authors.affiliation: Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, United States.
authors.forename: Ranjula
authors.initials: R
authors.lastname: Wijayatunge
authors.affiliation: Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, United States.
authors.forename: Liang-Fu
authors.initials: LF
authors.lastname: Chen
authors.affiliation: Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, United States.
authors.forename: Young May
authors.initials: YM
authors.lastname: Cha
authors.affiliation: Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, United States.
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Zannas
authors.affiliation: Program in Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, United States.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Frank
authors.affiliation: Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, United States. Electronic address: west@neuro.duke.edu.
authors.forename: Anne E
authors.initials: AE
authors.lastname: West
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001640:Bicuculline / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology*; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018721:Muscarinic Agonists / Q000633:toxicity; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010862:Pilocarpine / Q000633:toxicity; D026902:Potassium Channel Blockers / Q000494:pharmacology; D034622:RNA Interference / Q000502:physiology; D012640:Seizures / Q000139:chemically induced / Q000473:pathology*
chemical_list: D058787:GABA-A Receptor Antagonists; D018721:Muscarinic Agonists; D026902:Potassium Channel Blockers; D010862:Pilocarpine; D015761:4-Aminopyridine; D056484:Jumonji Domain-Containing Histone Demethylases; C523761:Kdm6b protein, mouse; D001640:Bicuculline
keywords: Activity-dependent; Chromatin regulation; Gene expression; Hippocampus; Histone lysine methylation; Jmjd3; Kdm6b; Neuronal survival