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.
van Essen
Dominic
D
Department of Cellular and Molecular Immunology, Max Planck Institute for Immunobiology, Stübeweg 51, 79108 Freiburg, Germany.
Zhu
Yina
Y
Saccani
Simona
S
D000818:Animals; D002460:Cell Line; D020868:Gene Silencing / Q000502:physiology*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000378:metabolism*; D020569:Proto-Oncogene Proteins c-rel / Q000235:genetics / Q000378:metabolism*
D006657:Histones; D016328:NF-kappa B; D020569:Proto-Oncogene Proteins c-rel; D010089:Oxidoreductases, N-Demethylating; C544113:kdm1b protein, mouse