INO80/SWR remodelers, including INO80, P400/TIP60, and SRCAP, have been viewed to regulate H2A.Z dynamics, but how they control specific gene expression remains unclear. Here, we reveal distinct phenotypes arising from short- and long-term perturbations following the depletion of INO80/SWR remodelers. We identified the direct target genes of INO80, P400, and SRCAP remodelers. Mechanistically, we found that INO80/SWR remodelers interact and facilitate the chromatin occupancy of the H2A.Zac reader protein BRD2, thereby elucidating the regulation of Pol II transcription by INO80/SWR remodelers. Additionally, while the degradation of P400 or SRCAP led to a reduction in H2A.Zac, INO80 depletion did not affect H2A.Zac occupancy but decreased the occupancy of P400 and SRCAP. Collectively, our findings suggest that INO80/SWR remodelers primarily regulate the chromatin landscape and influences BRD2 chromatin binding, thereby shedding light on their mechanisms in Pol II transcription regulation during development and disease.
© The Author(s) 2025. Published by Oxford University Press.