Dual role of PR-SET7-mediated H4K20me1 in the local regulation of RNA polymerase II promoter-proximal pausing [Gene Regulation]

January 23rd, 2014 by Kapoor-Vazirani, P., Vertino, P. M.

RNA polymerase II (Pol II) promoter-proximal pausing plays a critical role in post-initiation transcriptional regulation at many metazoan genes. We recently showed that histone H4 lysine 16 acetylation (H4K16Ac), mediated by the MSL complex, facilitates the release of paused Pol II. In contrast, H4 lysine 20 trimethylation (H4K20me3), mediated by SUV420H2, enforces Pol II pausing by inhibiting MSL recruitment. However, how H4K16Ac and H4K20me3 are locally regulated in Pol II pausing remains unclear. Here, we demonstrate that PR-SET7/SETD8, which monomethylates histone H4 lysine 20 (H4K20me1), controls H4K16Ac and H4K20me3, and in so doing regulates Pol II pausing dynamics. PR-SET7-mediated H4K20me1 is necessary for the recruitment of the MSL complex, subsequent H4K16Ac and release of Pol II into active elongation. Although dispensable for SUV420H2 recruitment, PR-SET7-mediated H4K20me1 is required for H4K20me3. Whereas depletion of SUV420H2 is sufficient to deplete H4K20me3 and relieve an H4K20me3-induced pause, pausing is maintained in the absence of PR-SET7 despite H4K20me3 depletion due to an inability to recruit the MSL complex in the absence of H4K20me1. These findings highlight the requirement for PR-SET7 and H4K20me1 in establishing both the H4K16Ac and H4K20me3 marks and points to a dual role in the local regulation of Pol II pausing.