GABPA Recruits the Integrator Endonuclease Complex to Promote Transcription Elongation

Transcription factors (TFs) coordinate gene regulatory programs essential for cell identity and fate, yet the mechanisms by which individual TFs modulate distinct stages of transcription remain incompletely understood. GABPA, an ETS family transcription factor, was recently identified as a critical regulator of naïve pluripotency in mouse embryonic stem cells (mESCs), but its molecular functions have remained elusive. Here, we employ an acute protein degradation system to dissect GABPA activity with high temporal resolution, enabling the identification of immediate transcriptional targets and mechanisms while avoiding secondary effects associated with conventional gene knockouts. We find that GABPA is essential for mESC viability through a previously unrecognized mechanism that is independent of its canonical heterotetrameric partner, GABPB. Mechanistically, GABPA physically engages the INTS4/9/11 endonuclease module of the Integrator complex to facilitate RNA polymerase II (Pol II) pause-release at ribosome biogenesis genes, promoting productive transcription elongation. Acute GABPA depletion leads to a marked reduction of gene body-associated Ser2-phosphorylated Pol II, indicative of defective elongation. In contrast, prolonged GABPA loss results in diminished chromatin accessibility and enhancer activity at pluripotency-associated loci. Together, these findings reveal dual temporally distinct roles for GABPA, an immediate function in transcriptional elongation and a later function in chromatin regulation. Our study redefines GABPA as a multifaceted transcriptional regulator acting independently of GABPB, and provides a framework for temporally resolved dissection of TF function in stem cell biology.