Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Nature. 2023 Mar;615(7951):339-348. doi: 10.1038/s41586-023-05780-8. Epub 2023 Mar 1.
Trimethylation of histone H3 lysine 4 (H3K4me3) is associated with transcriptional start sites and has been proposed to regulate transcription initiation. However, redundant functions of the H3K4 SET1/COMPASS methyltransferase complexes complicate the elucidation of the specific role of H3K4me3 in transcriptional regulation. Here, using mouse embryonic stem cells as a model system, we show that acute ablation of shared subunits of the SET1/COMPASS complexes leads to a complete loss of all H3K4 methylation. Turnover of H3K4me3 occurs more rapidly than that of H3K4me1 and H3K4me2 and is dependent on KDM5 demethylases. Notably, acute loss of H3K4me3 does not have detectable effects on transcriptional initiation but leads to a widespread decrease in transcriptional output, an increase in RNA polymerase II (RNAPII) pausing and slower elongation. We show that H3K4me3 is required for the recruitment of the integrator complex subunit 11 (INTS11), which is essential for the eviction of paused RNAPII and transcriptional elongation. Thus, our study demonstrates a distinct role for H3K4me3 in transcriptional pause-release and elongation rather than transcriptional initiation.
组蛋白 H3 赖氨酸 4 的三甲基化（H3K4me3）与转录起始位点相关联，并被提议调节转录起始。然而，H3K4 SET1/COMPASS 甲基转移酶复合物的冗余功能使得阐明 H3K4me3 在转录调控中的特定作用变得复杂。在这里，我们使用小鼠胚胎干细胞作为模型系统，表明 SET1/COMPASS 复合物的共享亚基的急性缺失会导致所有 H3K4 甲基化完全丧失。H3K4me3 的周转率比 H3K4me1 和 H3K4me2 更快，并且依赖于 KDM5 去甲基酶。值得注意的是，H3K4me3 的急性缺失对转录起始没有可检测的影响，但会导致转录产物广泛减少、RNA 聚合酶 II（RNAPII）暂停增加和延伸速度减慢。我们表明，H3K4me3 对于整合复合物亚基 11（INTS11）的招募是必需的，INTs11 对于暂停的 RNAPII 的逐出和转录延伸是必需的。因此，我们的研究表明 H3K4me3 在转录暂停释放和延伸中而不是在转录起始中具有独特的作用。
