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.

许多染色质修饰因子以迄今未知的间接方式调节基因表达。揭示这种间接基因调控的分子基础将有助于了解它们在基因调控和相关生物学过程中的确切作用。在这里，我们研究了通过调节组蛋白甲基转移酶Set1的表达间接调节基因表达的组蛋白修饰酶。通过无偏筛选组蛋白H3 / H4突变体库，我们确定了13个组蛋白取代突变，其中Set1和H3K4三甲基化（H3K4me3）的水平降低，而2个突变则具有Set1和H3K4me3的水平升高，这些突变集中在3个结构簇上。在这些取代中，H3K14A突变体大大降低了SET1转录和H3K4me3。H3K14在SET1启动子处被组蛋白乙酰转移酶Gcn5乙酰化，然后促进SET1转录以维持正常的H3K4me3水平。相反，组蛋白脱乙酰基酶Rpd3使H3K14脱乙酰基化以抑制SET1转录，从而降低H3K4me3水平，从而在H3K14ac和H3K4me3之间建立起动态的串扰。通过促进SET1的转录并维持H3K4me3的水平，Gcn5以间接的方式调节子集基因的转录。总体上，我们提出了一个模型，其中Gcn5促进染色质修饰剂的表达以调节组蛋白串扰和基因转录。