Various factors differentially recognize trimethylated histone H3 lysine 4 (H3K4me3) near promoters, H3K4me2 just downstream, and promoter-distal H3K4me1 to modulate gene expression. This methylation “gradient” is thought to result from preferential binding of the H3K4 methyltransferase Set1/complex associated with Set1 (COMPASS) to promoter-proximal RNA polymerase II. However, other studies have suggested that location-specific cues allosterically activate Set1. Chromatin immunoprecipitation sequencing (ChIP-seq) experiments show that H3K4 methylation patterns on active genes are not universal or fixed and change in response to both transcription elongation rate and frequency as well as reduced COMPASS activity. Fusing Set1 to RNA polymerase II results in H3K4me2 throughout transcribed regions and similarly extended H3K4me3 on highly transcribed genes. Tethered Set1 still requires histone H2B ubiquitylation for activity. These results show that higher-level methylations reflect not only Set1/COMPASS recruitment but also multiple rounds of transcription. This model provides a simple explanation for non-canonical methylation patterns at some loci or in certain COMPASS mutants.

各种因素差异地识别启动子附近的三甲基化组蛋白H3赖氨酸4（H3K4me3），下游的H3K4me2和远端的H3K4me1来调节基因表达。该甲基化“梯度”被认为是由于与Set1（COMPASS）相关的H3K4甲基转移酶Set1 /复合物与启动子近端RNA聚合酶II的优先结合而产生的。但是，其他研究表明，位置特定的线索会变构地激活Set1。染色质免疫沉淀测序（ChIP-seq）实验表明，活性基因上的H3K4甲基化模式不是普遍的或固定的，并且会随着转录延伸率和频率的变化以及COMPASS活性的降低而发生变化。将Set1与RNA聚合酶II融合会在整个转录区域产生H3K4me2，并在高度转录的基因上类似地扩展H3K4me3。系留Set1仍需要组蛋白H2B泛素化才能发挥作用。这些结果表明，更高水平的甲基化不仅反映了Set1 / COMPASS募集，而且还反映了多轮转录。该模型为某些基因座或某些COMPASS突变体中的非规范甲基化模式提供了简单的解释。