GABPA recruits the Integrator endonuclease complex to promote transcription elongation

GABPA, an ETS family TF, is crutial for naïve pluripotency in mouse preimplantation development, but its molecular functions have remained elusive. Using an acute protein degradation system, we dissect GABPA activity with high temporal resolution, identifying 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 productive elongation of RNA polymerase II (Pol II) at ribosome biogenesis genes. Acute GABPA loss causes promoter-proximal Pol II accumulation and reduces gene body Ser2-phosphorylated Pol II, indicative of elongation defects, while prolonged depletion diminishes chromatin accessibility and enhancer activity at pluripotency-associated loci.