The histone lysine demethylase Kdm6b is required for activity-dependent preconditioning of hippocampal neuronal survival.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Wijayatunge, R; Chen, L-F; Cha, YM; Zannas, AS; Frank, CL; West, AE

Published Date

  • July 2014

Published In

Volume / Issue

  • 61 /

Start / End Page

  • 187 - 200

PubMed ID

  • 24983519

Pubmed Central ID

  • PMC4138546

Electronic International Standard Serial Number (EISSN)

  • 1095-9327

Digital Object Identifier (DOI)

  • 10.1016/j.mcn.2014.06.008


  • eng

Conference Location

  • United States