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


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

  • 24983519

Electronic International Standard Serial Number (EISSN)

  • 1095-9327

Digital Object Identifier (DOI)

  • 10.1016/j.mcn.2014.06.008


  • eng

Conference Location

  • United States