With mice with two dads, crystal clear images of dying stars, and the rise of ChatGPT being daily news items, does anything make you “pause for thought” these days? A stunning study from reflective researchers just might! They provide insight into an epigenetic enigma surrounding the transcriptional role of a histone modification by reporting how H3K4 methylation loss modulates RNAPII pause-release at gene promoters and transcriptional elongation but not initiation.
Pensive epigenetic detectives led by Kristian Helin had cogitated over the hypothesis that the H3K4me3 modification present at transcriptional start sites may regulate transcription initiation; however, redundancies in the SET1/COMPASS methyltransferase complexes that support H3K4me3 formation made deciphering a role for this modification in transcriptional regulation a chin-scratching problem. After some deliberation, they decided that the targeted degradation of shared SET1/COMPASS complex subunits (prompting the loss of all H3K4 methylation) may provide the solution!
Let’s not pause for thought and quickly hear what Wang and colleagues discovered in their new Zen-like study:
- Targeted degradation of DPY30 or RBBP5 core SET1/COMPASS components using tag-based degradation prompts the loss of H3K4 methylation and mRNA synthesis and slower proliferation in differentiating mouse embryonic stem cells
- The more evident turnover of H3K4me3 (compared to H3K4me1 and H3K4me2) at early timepoints after acute DPY30/RBBP5 loss suggests that transcription requires H3K4me3
- H3K4me3 turnover depends on the activity of the KDM5A and B demethylases
- In detail, H3K4me3 loss does not lead to alterations in RNAPII pre-initiation complex formation, pre-initiation complex association with transcriptional start sites, RNAPII loading, or transcriptional initiation
- Instead, acute H3K4me3 loss inhibits the release of paused RNAPII at gene promoters and slows elongation, thereby reducing the levels of gene transcription
- Further analysis demonstrates that the H3K4me3 modification typically recruits INTS11 to aid the eviction of paused RNAPII from gene promoters and enhance transcriptional elongation
These researchers didn’t pause for thought when faced with a chromatin conundrum; instead, their well-thought-out research now suggests a vital role for the H3K4me3 modification at transcriptional start sites in transcriptional pause-release and elongation rather than transcriptional initiation. Their next steps include determining the molecular mechanism regulating INTS11 recruitment and deciphering INTS11’s function in elongation.
Study leader Professor Kristian Helin shares, “We have solved a 20-year-old puzzle by discovering how a well-known epigenetic modification controls gene expression. Because the enzymes determining the level of H3K4me3 in the cell frequently are found mutated in cancer, our studies could have implications for understanding and treating cancer.”
Don’t pause for thought too long; see all the details at Nature, March 2023.