RNA polymerase II pausing during development

Abstract

The rapid expansion of genomics methods has enabled developmental biologists to address fundamental questions of developmental gene regulation on a genome-wide scale. These efforts have demonstrated that transcription of developmental control genes by RNA polymerase II (Pol II) is commonly regulated at the transition to productive elongation, resulting in the promoter-proximal accumulation of transcriptionally engaged but paused Pol II prior to gene induction. Here we review the mechanisms and possible functions of Pol II pausing and their implications for development.

The Central Region of the Drosophila Co-repressor Groucho as a Regulatory Hub

“…This finding is in agreement with the hypothesis that Pol II pausing is one mechanism to repress gene expression (75,76). We note that our proteomic screen revealed the Pol II C-terminal domain kinase Cdk12 as a Gro-interacting protein (supplemental Table S1).…”

Nup98 promotes antiviral gene expression to restrict RNA viral infection in Drosophila

“…In the absence of Nup98, along with the loss of RNAPII S5P, these antiviral genes are no longer efficiently induced, resulting in elevated levels of viral infection. This model is consistent with the recent results demonstrating recruitment of Nup98 to the promoter of developmentally regulated genes independent of transcription elongation, because Nup98 recruitment is insensitive to flavopiridol treatment (19), and that many developmental genes are known to be regulated at the level of pausing (8,37). Consistent with the hypothesis that Nup98 is a specific transcription activator, it also has been demonstrated that Nup98 interacts with histone-modifying enzymes CBP/p300 and histone deacetylases (45,46).…”

“…Based on these findings, and given the fact that many developmental and immune genes are regulated by transcriptional pausing (4,6,8,14,23,24), we hypothesized that Nup98 also may regulate virus-induced antiviral genes. We found that Nup98 plays a broadly antiviral role in insects; cells or adult flies depleted of Nup98 are more susceptible to infection against a panel of disparate RNA viruses.…”

“…This response is divided into two stages; within minutes, a rapid primary response independent of new protein synthesis is initiated, which instructs the downstream translationdependent secondary response (2,5). Many primary response genes have active chromatin marks and features of transcriptional pausing, including high occupancy of the initiating form of RNA polymerase II (RNAPII), S5 phosphorylated (S5P) (2,4,6), along with negative elongation factor complex (NELF) and DRB Sensitivity-Inducing Factor complex (DSIF), which prevent transcriptional elongation (4,(6)(7)(8)(9)(10). Paused RNAPII can be activated by the positive transcription elongation factor b (P-TEFb) in a stimulusdependent manner, which phosphorylates NELF, DSIF, and RNAPII to release the pause and promote transcriptional elongation and thus the production of mature mRNAs (9,(11)(12)(13).…”

The Promises of the Novel Connection Between HEXIM and Hedgehog Signalling

“…Disrupting HEXIM and PTEFb physical interactions releases free P-TEFb and the stalled transcription can resume very quickly. This nice mechanism allows a fast transcriptional response as well as a strong transcriptional repression mechanism depending to the context [4]. Therefore, and somewhat counter intuitively, the transcriptional regulation of these genes may not be dependent on the complex recruitment of a cohort of very specific transcription factors, and the hunt for specific transcription factors responsible for their very fast transcriptional response may be inconclusive.…”