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 lysine27-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.

Kdm6b and Pmepa1 as Targets of Bioelectrically and Behaviorally Induced Activin A Signaling

“…Beyond KDM6B's requirement for neural lineage commitment and neuronal differentiation [30][31][32]48], its expression and function in the adult CNS are largely unexplored. A recent study found that Kdm6b is upregulated by pilocarpine-induced seizures in the hippocampus and contributes to activity-induced preconditioning of neuronal survival in cultured hippocampal neuron [33]. We report here that ECS caused a significant enrichment of SMAD2/3 binding to the murine Kdm6b gene in the hippocampus (Fig.…”

“…This epigenetic regulator had previously been associated with SMAD signaling and neuronal differentiation [30][31][32][33] and would thus be well suited to translate enhanced activin signaling into chromatin remodeling and increased transcriptional activity. Kdm6b mRNA levels increased significantly 2 and 6 h after ECS and returned to baseline at 12 h (Fig.…”

Alcohol-induced suppression of KDM6B dysregulates the mineralization potential in dental pulp stem cells

“…Recent studies show that KDM6B is involved in the control of calcium-induced differentiation [52], regulates osteoblast differentiation [53], contributes to neuronal survival and differentiation [54], odontogenic differentiation of DPSCs [19], and osteogenic differentiation of human BMSCs [18]. It has been reported that calcium-induced differentiation leads to increased binding of KDM6B and erasure of repressive marks such as H3K27me3 [52].…”

Definition of a Bidirectional Activity-Dependent Pathway Involving BDNF and Narp

“…While transcription factors were originally identified as immediate early genes (IEGs) induced by growth factors, a growing list of diverse proteins has been discovered as activity-dependent genes. These include cytoskeletal proteins, such as Arc (Lyford et al, 1995), chromatin modification enzymes (Wijayatunge et al, 2014) and extracellular proteases, such as tissue-plasminogen activator (Qian et al, 1993). How the activities of immediate early genes are coordinated and inter-connected is an open question.…”