H3K4me3 regulates RNA polymerase II promoter-proximal pause-release

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.

BRWD3 promotes KDM5 degradation to maintain H3K4 methylation levels

“…Taken together, we conclude that BRWD3 binding sites show significant overlap with KDM5 sites genome wide. Given that KDM5 can sequentially remove methyl group from H3K4me3 to convert it to H3K4me2 and further to H3K4me1, we hypothesize that BRWD3 influences H3K4me3 levels by regulating KDM5 activity (13, 42).…”

“…Given that BRWD3 controls KDM5 stability, we predict that KDM5 is overactive in BRWD3-depleted cells. In vitro, KDM5 demethylases preferentially target H3K4me3 and to a lesser extent H3K4me2 with little to no activity on H3K4me1 (13,42). Therefore, we predict that overactive KDM5 removes methyl groups from H3K4me3, ultimately resulting in increased H3K4me1 levels and explaining the altered levels of H3K4 methylation in BRWD3 depleted cells.…”

“…H3K4me3 is associated with actively transcribed genes and can enhance binding of TFIID to promoters (47, 48). Recently, new evidence suggested that H3K4me3 has role in regulating RNA polymerase II promoter-proximal pause-release (42). H3K4me1, on the other hand, is enriched at enhancers and may serve to recruit chromatin modifying proteins to enable enhancer activity (7, 49).…”

The BOD1L subunit of the mammalian SETD1A complex sustains the expression of DNA damage repair genes despite restraining H3K4 trimethylation

“…These discoveries promoted investigations of H3K4me3 as an epitope in promoter architecture and the mechanics of transcriptional initiation. The identification of the TAF3 subunit of TFIID as an H3K4me3 binder secured these investigations(Vermeulen et al 2007;Lauberth et al 2013), which has been recently extended by the identification of a role for H3K4me3 in promoter-proximal pause-release of RNA polymerase II(Wang et al 2023).…”

Dynamics of the epigenetic landscape during development and in response to drought stress in sorghum

“…Histone acetylation and H3K4me3 tend to mark transcription start site (TSS) regions (a short region immediately downstream from TSS), while H3K36me3 are more likely to be enriched in gene body regions (a longer region from TSS to transcription end site (TES)) [1][2][3], suggesting that they are involved in governing different processes of gene transcription. Histone acetylation and H3K4me3 have been reported to be involved in transcription initiation by affecting the assembly of pre-initiation complex (PIC), or stimulating the transition from initiation to elongation [4][5][6][7]. H3K36me3, generally considered as a hallmark of transcription elongation, is required for co-transcriptional splicing [2,8,9].…”