Histone acetyltransferase Gcn5 regulates gene expression by promoting the transcription of histone methyltransferase SET1

Many chromatin modifying factors regulate gene expression in an as-yet-unknown indirect manner. Revealing the molecular basis for this indirect gene regulation will help understand their precise roles in gene regulation and associated biological processes. Here, we studied histone modifying enzymes that indirectly regulate gene expression by modulating the expression of histone methyltransferase, Set1. Through unbiased screening of the histone H3/H4 mutant library, we identified 13 histone substitution mutations with reduced levels of Set1 and H3K4 trimethylation (H3K4me3) and 2 mutations with increased levels of Set1 and H3K4me3, which concentrate at 3 structure clusters. Among these substitutions, the H3K14A mutant substantially reduces SET1 transcription and H3K4me3. H3K14 is acetylated by histone acetyltransferase Gcn5 at SET1 promoter, which then promotes SET1 transcription to maintain normal H3K4me3 levels. In contrast, the histone deacetylase Rpd3 deacetylates H3K14 to repress SET1 transcription and hence reduce H3K4me3 levels, establishing a dynamic crosstalk between H3K14ac and H3K4me3. By promoting the transcription of SET1 and maintaining H3K4me3 levels, Gcn5 regulates the transcription of a subset gene in an indirect manner. Collectively, we propose a model wherein Gcn5 promotes the expression of chromatin modifiers to regulate histone crosstalk and gene transcription.