Growth factor-induced activation of MSK2 leads to phosphorylation of H3K9me2S10 and corresponding changes in gene expression [CUT&RUN]

Extracellular signals are transmitted through kinase cascades to modulate gene expression, but it remains unclear how epigenetic changes in chromatin architecture may regulate this response. Here we provide evidence supporting a mechanism through which growth factor-responsive genes located within H3K9me2-marked heterochromatin domains are made available for transcriptional activation via phosphorylation of the adjacent histone H3 serine 10 residue following growth factor signaling. Imaging and proteomic approaches show that Epidermal Growth Factor (EGF) stimulation results in H3K9me2S10 phosphorylation, which occurs in genomic regions enriched for regulatory enhancers of EGF-responsive genes. We also demonstrate that the EGF-induced increase in H3K9me2S10ph is dependent on the nuclear kinase MSK2, and a subset of EGF-induced genes is dependent on MSK2 for transcription. Taken together, our work indicates that growth factor-induced changes in chromatin state can mediate the activation of downstream genes. Overall design: CUT&RUN sequencing for H3K9me2S10ph in human IMR90 lung fibroblast cells, serum starved for 24 hours and treated with either PBS or 750pM EGF for 30 minutes.