Waves of chromatin modifications in mouse dendritic cells in response to LPS stimulation

Alexis Vandenbon, Yutaro Kumagai, Mengjie Lin, Yutaka Suzuki, Kenta Nakai

The importance of transcription factors (TFs) and epigenetic modifications in the control of gene expression is widely accepted. However, causal relationships between changes in TF binding, histone modifications, and gene expression during the response to extracellular stimuli are not well understood. Here, we analyze the ordering of these events on a genome-wide scale in dendritic cells in response to lipopolysaccharide (LPS) stimulation. Using a ChIP-seq time series dataset, we find that the LPS-induced accumulation of different histone modifications follows clearly distinct patterns. Increases in H3K4me3 appear to coincide with transcriptional activation. In contrast, H3K9K14ac accumulates early after stimulation, and H3K36me3 at later time points. Integrative analysis with TF binding data reveals potential links between TF activation and dynamics in histone modifications. Especially, LPS-induced increases in H3K9K14ac and H3K4me3 are associated with binding by STAT1/2 and were severely impaired in Stat1-/- cells. While the timing of short-term changes of some histone modifications coincides with changes in transcriptional activity, this is not the case for others. In the latter case, dynamics in modifications more likely reflect strict regulation by stimulus-induced TFs and their interactions with chromatin modifiers.