小柯机器人

美国纪念斯隆凯特琳癌症研究中心Kristian Helin小组发现，H3K4me3调控RNA聚合酶II启动子-近端的暂停-释放。该项研究成果于2023年3月1日在线发表在《自然》杂志上。

研究人员使用小鼠胚胎干细胞作为模型系统，发现SET1/COMPASS复合体的共同亚基的急性去除导致所有组蛋白H3第4位赖氨酸（H3K4）甲基化的完全丧失。H3K4me3的转变比H3K4me1和H3K4me2的转变更快，并依赖于KDM5脱甲基酶。值得注意的是，H3K4me3的急性缺失对转录起始没有可察觉的影响，但会导致转录输出的广泛减少，RNA聚合酶II（RNAPII）暂停的增加和延长的减慢。结果表明，H3K4me3是招募整合子复合体亚单位11（INTS11）所需的，而后者是驱逐暂停的RNAPII和转录延伸的关键。因此，这项研究表明，H3K4me3在转录暂停释放和延伸中具有独特的作用，而非转录启动。

据悉，H3K4me3与转录起始位点有关，并被认为是调节转录起始的。然而，H3K4 SET1/COMPASS甲基转移酶复合物的冗余功能使阐明H3K4me3在转录调控中的具体作用变得复杂。

附：英文原文

Title: H3K4me3 regulates RNA polymerase II promoter-proximal pause-release

Author: Wang, Hua, Fan, Zheng, Shliaha, Pavel V., Miele, Matthew, Hendrickson, Ronald C., Jiang, Xuejun, Helin, Kristian

Issue&Volume: 2023-03-01

Abstract: Trimethylation of histone H3 lysine 4 (H3K4me3) is associated with transcriptional start sites and has been proposed to regulate transcription initiation1,2. However, redundant functions of the H3K4 SET1/COMPASS methyltransferase complexes complicate the elucidation of the specific role of H3K4me3 in transcriptional regulation3,4. 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.

DOI: 10.1038/s41586-023-05780-8

Source: https://www.nature.com/articles/s41586-023-05780-8

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html