Summary Recent genome-wide studies have demonstrated pausing of RNA polymerase II (Pol II) occurred on many vertebrate genes. By genetic studies in the zebrafish tif1γ mutant moonshine we found that loss of function of Pol II-associated factors PAF or DSIF rescued erythroid gene transcription in tif1γ-deficient animals. Biochemical analysis established physical interactions among TIF1γ, the blood-specific SCL transcription complex, and the positive elongation factors p-TEFb and FACT. ChIP assays in human CD34+ cells supported a TIF1γ-dependent recruitment of positive elongation factors to erythroid genes to promote transcription elongation by counteracting Pol II pausing. Our study establishes a mechanism for regulating tissue cell fate and differentiation through transcription elongation.

Promoter-proximal pausing by RNA polymerase II (Pol II) is a well-established mechanism to control the timing, rate, and possibly the magnitude of transcriptional responses. Recent studies have shown that cellular signaling pathways can regulate gene transcription and signaling outcomes by controlling Pol II pausing in a wide array of biological systems. Identification of the proteins and small molecules that affect the establishment and release of paused Pol II is shedding new light on the mechanisms and biology of Pol II pausing. This review will focus on the interplay between cellular signaling pathways and Pol II pausing during normal development and under disease conditions.