A Feed-Forward Circuit Controlling Inducible NF-κB Target Gene Activation by Promoter Histone Demethylation

Activation of transcription from a silenced state is crucial to achieve specific gene expression in many biological contexts. Methylation of lysine 9 on histone H3 (H3K9) is widely associated with transcriptional silencing, and its disappearance is linked to the activation of several inflammatory genes by NF-κB. Here we describe that this event is controlled by a feed-forward circuit catalyzed by the activity of the histone demethylase Aof1 (also known as Lsd2/Kdm1b). We find that Aof1 is required for removal of dimethyl H3K9 at specific promoters, and thereby it controls stimulus-induced recruitment of NF-κB and gene expression. However, Aof1 is itself recruited by interaction with the c-Rel subunit of NF-κB, which is found at low levels associated with promoters in unstimulated cells. Thus, at these tightly regulated genes, NF-κB functions both as a transcriptional activator and as an upstream targeting signal that marks promoters to be derepressed by histone demethylation. [Display omitted] ► Aof1 activity is required for expression of a subset of inflammatory genes ► Aof1 demethylates H3K9me2 at the promoter regions of target genes ► Demethylation of H3K9 controls stimulus-induced recruitment of NF-κB proteins ► c-Rel binds to inactive promoters and acts as a targeting signal for Aof1