Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.7.6 (RNA polymerase)
 34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Many human genes exhibit evidence of initiated RNA polymerase II (Pol II) at their promoters, despite a lack of significant full-length transcript. Such genes exhibit promoter-proximal "pausing," wherein initiated Pol II accumulates just downstream of the transcription start site due to a rate-limiting step mediating the transition to elongation. The mechanisms that regulate the escape of Pol II from pausing and the relationship to chromatin structure remain incompletely understood. Recently, we showed that CpG island hypermethylation and epigenetic silencing of TMS1/ASC in human breast cancers are accompanied by a local shift from histone H4 lysine 16 acetylation (H4K16Ac) to H4 lysine 20 trimethylation (H4K20me3). Here, we show that hMOF-mediated H4K16Ac and SUV420H2-mediated H4K20me3 play opposing roles in the regulation of Pol II pausing. We found that H4K16Ac promoted the release of Pol II from pausing through the recruitment of BRD4 and pTEFb. Aberrant methylation of CpG island DNA blocked Pol II recruitment to gene promoters. Whereas the inhibition of DNA methylation allowed for the reassociation and initiation of Pol II at the TMS1 promoter, Pol II remained paused in the presence of H4K20me3. Combined inhibition of H4K20me3 and DNA methylation resulted in the rerecruitment of hMOF and subsequent H4K16Ac, release of Pol II into active elongation, and synergistic reactivation of TMS1 expression. Marking by H4K20me3 was not restricted to TMS1 but also occurred at other genes independently of DNA methylation, where it similarly imposed a block to Pol II promoter escape through a mechanism that involved the local inhibition of H4K16Ac. These data indicate that H4K20me3 invokes gene repression by antagonizing hMOF-mediated H4K16Ac and suggest that overcoming Pol II pausing might be a rate-limiting step in achieving tumor suppressor gene reactivation in cancer therapy.
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PMID:SUV420H2-mediated H4K20 trimethylation enforces RNA polymerase II promoter-proximal pausing by blocking hMOF-dependent H4K16 acetylation. 2132 Oct 83

RNA polymerase II (Pol II) promoter-proximal pausing plays a critical role in postinitiation transcriptional regulation at many metazoan genes. We showed recently 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 the balance between H4K16Ac and H4K20me3 is locally regulated remains unclear. Here, we demonstrate that PR-SET7/SETD8, which monomethylates histone H4 lysine 20 (H4K20me1), controls both H4K16Ac and H4K20me3 and in doing so, regulates Pol II pausing dynamics. We find that 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. Although 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 because of 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 point to a dual role in the local regulation of Pol II pausing.
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PMID:A dual role for the histone methyltransferase PR-SET7/SETD8 and histone H4 lysine 20 monomethylation in the local regulation of RNA polymerase II pausing. 2445 45