Cell-Type-Specific Control of Enhancer Activity by H3K9 Trimethylation

SummaryCell-type-specific control of gene expression is critical for the development of multicellular organisms. To investigate the mechanisms which underlie this, we have studied the regulation of the model genes Mdc and Il12b, whose stimulus-induced expression is tightly restricted to specific cells of the immune system. Surprisingly, we find that neither the promoter nor the enhancer sequences of these genes are sufficient to direct this cell-type specificity. Instead, the activities of upstream enhancers are repressed in nonexpressing cells by high levels of trimethylated H3K9 in their flanking regions. Genome-wide analysis indicates that this manner of regulation is shared by numerous enhancers of cell-type-specific genes. In dendritic cells and macrophages, the stimulus-induced demethylase Jmjd2d controls H3K9me3 levels at these regions, and is thereby required for Mdc and Il12b transcription. By experimentally assaying multiple enhancers in a variety of cell types, we show that regulation by H3K9me3 is a widely used mechanism which imparts specificity to the activities of otherwise broadly functional enhancers.

Graphical AbstractFigure optionsDownload high-quality image (132 K)Download as PowerPoint slideHighlights
► Enhancers of model inflammatory genes are regulated by neighboring H3K9me3
► The demethylase JmjD2d regulates H3K9me3 levels around enhancers upon stimulation
► JmjD2d is required for cell-type-specific expression of a subset of NF-κB target genes
► 4H3K9me3 confers cell-type specificity on broadly functional enhancers throughout the genome