FOXP3 Orchestrates H4K16 Acetylation and H3K4 Trimethylation for Activation of Multiple Genes by Recruiting MOF and Causing Displacement of PLU-1

SummaryBoth H4K16 acetylation and H3K4 trimethylation are required for gene activation. However, it is still largely unclear how these modifications are orchestrated by transcriptional factors. Here, we analyzed the mechanism of the transcriptional activation by FOXP3, an X-linked suppressor of autoimmune diseases and cancers. FOXP3 binds near transcriptional start sites of its target genes. By recruiting MOF and displacing histone H3K4 demethylase PLU-1, FOXP3 increases both H4K16 acetylation and H3K4 trimethylation at the FOXP3-associated chromatins of multiple FOXP3-activated genes. RNAi-mediated silencing of MOF reduced both gene activation and tumor suppression by FOXP3, while both somatic mutations in clinical cancer samples and targeted mutation of FOXP3 in mouse prostate epithelial cells disrupted nuclear localization of MOF. Our data demonstrate a pull-push model in which a single transcription factor orchestrates two epigenetic alterations necessary for gene activation and provide a mechanism for somatic inactivation of the FOXP3 protein function in cancer cells.

Graphical AbstractFigure optionsDownload high-quality image (229 K)Download as PowerPoint slideHighlights
► FOXP3 recruits MOF and enhances H4K16ac at FOXP3-binding sites
► MOF-FOXP3 complex is disrupted by somatic mutations of FOXP3 in cancer samples
► FOXP3 facilitates H3K4me3 of multiple genes by displacing PLU-1
► Activation of multiple FOXP3 targets by pull-push of histone modification enzymes