Cfp1 is required for gene expression-dependent H3K4 trimethylation and H3K9 acetylation in embryonic stem cells

Trimethylation of histone H3 lysine 4 (H3K4me3) accumulates at promoters in a gene activity-dependent manner. The Set1 complex is responsible for most H3K4me3 in somatic cells and contains the conserved subunit Cfp1, which is implicated in targeting the Set1 complex to CpG islands in mammals. In mouse embryonic stem cells, Cfp1 is necessary for H3K4me3 accumulation at constitutively active gene promoters, but is not required to maintain steady-state transcription of the associated gene.

Here we show that Cfp1 is instrumental for targeting H3K4me3 to promoters upon rapid transcriptional induction in response to external stimuli. Surprisingly, H3K4me3 accumulation is not required to ensure appropriate transcriptional output but rather plays gene-specific roles. We also show that Cfp1-dependent H3K4me3 deposition contributes to H3K9 acetylation genome-wide, suggesting that Cfp1-dependent H3K4me3 regulates overall H3K9 acetylation dynamics and is necessary for histone acetyl transferase recruitment. Finally, we observe increased antisense transcription at the start and end of genes that require Cfp1 for accurate deposition of H3K4me3 and H3K9ac.

Our results assign a key role for Cfp1 in establishing a complex active promoter chromatin state and shed light on how chromatin signaling pathways provide context-dependent transcriptional outcomes.