A ZBTB26 –Integrator Axis Mediates Targeted Transcriptional Activation

The Integrator complex is primarily known to attenuate transcription by inducing premature termination of paused RNA polymerase II (RNAPII) and restraining pause release through its endonuclease and phosphatase activities. However, the mechanisms that govern Integrator recruitment to chromatin and direct gene-specific transcriptional programs in response to external stimuli and diverse biological contexts remain poorly understood. In particular, the regulatory functions of the Integrator auxiliary or arm module (INTS10/13/14/15) are the least characterized. Here, we identify ZBTB26 as an interactor of the Integrator auxiliary module via INTS10 and INTS13, demonstrate its ability to directly bind a specific DNA motif, and show that it co-occupies select promoters and enhancers with Integrator and active histone markers across the genome. We demonstrate that ZBTB26 is required for the recruitment of Integrator to its target loci, including genes involved in stimulus response, development, and differentiation. Importantly, the ZBTB26-Integrator axis sustains the active state of specific promoters and enhancers and drives defined gene transcriptional programs. Our findings reveal a transcription factor-like mechanism of targeted gene regulation mediated by ZBTB26-Integrator binding, extending the functional paradigm of Integrator beyond its canonical catalytic roles.