Gene expression is far more than simply turning genes on or off. Shortly after transcription begins, RNA Pol II pauses near gene promoters before entering productive elongation. Although the endonuclease module of the Integrator complex has emerged as an important regulator of transcription, including productive elongation, it lacks intrinsic DNA-binding activity. How Integrator is selectively targeted to specific genes to exert its regulatory functions has remained a fundamental unanswered question.
In a study published in Science Bulletin , a team led by Chunxia Zhang at the Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, identified the transcription factor GABPA as the missing link. They found that GABPA directly recruits the Integrator complex. Biochemical, structural, and functional analyses confirmed that GABPA directly interacts with the endonuclease module of the Integrator complex, and recruits it to promoter regions, enabling Pol II to transition into productive transcription elongation.
The study expands the conventional view of GABPA. Although GABPA has long been known to function with its partner GABPB, depletion of GABPB1 and GABPB2 produced only modest effects compared with the rapid loss of cell viability caused by GABPA depletion, suggesting that this newly identified role of GABPA is largely independent of its canonical partner.
To capture GABPA's primary functions before secondary cellular responses emerged, the researchers established an acute protein degradation system capable of eliminating GABPA within an hour. Genome-wide analyses captured the earliest transcriptional consequences of GABPA loss. Within the first hour, transcription of genes involved in ribonucleoprotein biogenesis declined markedly, accompanied by the reduced Integrator occupancy at their promoters, and impaired Pol II progression into gene bodies. Notably, chromatin accessibility and active histone marks stayed unchanged during this early period, indicating that defective transcription elongation is a primary consequence of GABPA loss.
"We were surprised to find that GABPA does not stop working once transcription begins," Zhang said. "Beyond recognizing DNA and initiating gene expression, it also recruits Integrator to help RNA Pol II move into productive elongation." The findings redefine the role of classical transcription factors, showing that they can regulate not only select gene expression programs, but also directly control the transition of RNA Pol II to productive elongation. More broadly, the study established a direct molecular link between sequence-specific DNA recognition and the transcription elongation machinery, providing new insights into how gene expression programs are orchestrated during cell fate determination.
Science Bulletin
Experimental study