Alexis Vandenbon^1,2$*, Yutaro Kumagai^3,4$, Mengjie Lin⁵, Yutaka Suzuki⁵, Kenta Nakai⁶*

(1 Institute for Frontier Life and Medical Sciences, Kyoto University. 2 Institute for Liberal Arts and Sciences, Kyoto University. 3 Immunology Frontier Research Center, Osaka University. 4 Biotechnology Research Institute for Drug Discovery, National Institute of Advanced Industrial Science and Technology. 5 Graduate School of Frontier Sciences, The University of Tokyo. 6 The Institute of Medical Science, The University of Tokyo)

$ Equal contribution

* To whom correspondence should be addressed. Email: alexisvdb*infront.kyoto-u.ac.jp, knakai*ims.u-tokyo.ac.jp. (Replace the ∗ with @)

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

Genome Biology (2018), link    DOI: 10.1186/s13059-018-1524-z

 Background: 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.
Results: 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.
Conclusions: 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.

Figure 1: Snapshots of our data around the Il6 promoter showing the difference in the timing of events. Transcription from the Il6 promoter is induced rapidly after LPS stimulation (0.5h). At the same time, H3K9K14ac starts to accumulate. The level of H3K4me3 increases between 1-2h after stimulation. Finally, the accumulation of H3K36me3 at the promoter starts even later (around 6h). The ordering of these events is representative of genome-wide tendencies.

Figure 2: (left) A schematic model based on our findings. Following stimulation, a gene can move from an inactive to an active chromatin state. During this transition, different histone modifications are established following different patterns. The timing of these events is defined by their dependency on primary and secondary regulators. (right) As an example, we found that LPS-induced increases in H3K94K14ac are especially strong around STAT1 binding sites. In Stat1^-/- cells, the signal is completely abrogated. Thus, STAT1 binding defines both the location and the timing of H3K4K19 acetylation.