biostudies-literatureWang HNCI NIH HHSNIH HHS339-348https://www.ebi.ac.uk/biostudies/studies/S-EPMC9995272biostudies-literatureUnknown615(7951)Trimethylation of histone H3 lysine 4 (H3K4me3) is associated with transcriptional start sites and has been proposed to regulate transcription initiation^1,2. However, redundant functions of the H3K4 SET1/COMPASS methyltransferase complexes complicate the elucidation of the specific role of H3K4me3 in transcriptional regulation^3,4. 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 NatureH3K4me3 regulates RNA polymerase II promoter-proximal pause-release.PMC9995272S10 OD010598R01 CA204232P30 CA008748R01 CA166413R01 CA258622Miele MHelin KFan ZJiang XShliaha PVWang HHendrickson RCfalseH3K4me3 regulates RNA polymerase II promoter-proximal pause-release.Trimethylation of histone H3 lysine 4 (H3K4me3) is associated with transcriptional start sites and has been proposed to regulate transcription initiation^1,2. However, redundant functions of the H3K4 SET1/COMPASS methyltransferase complexes complicate the elucidation of the specific role of H3K4me3 in transcriptional regulation^3,4. 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 2023-01-01T00:00:00Z2023 Mar2026-05-28T18:39:24.205Z2025-02-19T04:44:10.105ZS-EPMC99952723685955010.1038/s41586-023-05780-8