Distinct roles of the two SEC scaffold proteins, AFF1 and AFF4, in regulating RNA Pol II transcription elongation

Abstract

The P-TEFb-containing super elongation complex (SEC) plays the essential role in transcriptional elongation control. The AF4/FMR2 family members AFF1 and AFF4 are the central scaffold proteins of SEC, associated with different human diseases. However, their specific roles in transcriptional control remain unclear. Here, we report that AFF1 and AFF4 show distinct genomic distribution patterns around TSS. AFF1 binds upstream of TSS, while AFF4 is enriched downstream of TSS. Pol II occupancies are reduced genome-widely after depletion of AFF1, but not AFF4. Interestingly, in a subset of active genes with broad AFF4 binding signature, AFF4 disruption causes slow elongation and early termination, while AFF1 deletion mirrors the transcriptional defects observed in the fast Pol II mutant. Furthermore, AFF4 knockdown leads to increased AFF1 levels at chromatin, and vice versa. In summary, our data demonstrate that AFF1 and AFF4 function, to some extent, antagonistically to ensure proper Pol II transcription.

SEC: A core hub during cell fate alteration

“…Furthermore, the depletion of AFF4 has been correlated with a deceleration in transcription elongation speed and premature termination of transcription. Conversely, insufficiency in AFF1 expedites transcription elongation and induces transcriptional readthrough 24 . These findings highlight the nuanced and precise regulation of Pol II pause release by the unique functions of AFF4 and AFF1, despite both serving as scaffolds for SEC.…”

“…Che et al. reported that AFF1 primarily localizes upstream of TSS, while AFF4 is positioned downstream 24 . Furthermore, the depletion of AFF4 has been correlated with a deceleration in transcription elongation speed and premature termination of transcription.…”

“…It is noteworthy that despite AFF4 and AFF1 both serving as scaffolds for SEC, their detailed regulation mechanisms in the transcription process are evidently distinct (Figure 1). 24 …”