RNA fine-tunes KAT5 activity to shape chromatin acetylation during active transcription [seCLIP-seq]

Although the chromatin recruitment of KAT5 and its associated NuA4/TIP60 complex is well characterized, the molecular mechanisms that regulate its catalytic activity are still largely unknown. Here, we identify RNA as a direct and reversible modulator of KAT5 activity.

Using single-end enhanced crosslinking and immunoprecipitation sequencing (seCLIP-seq), we find that KAT5 binds RNA in cells with a strong preference for GC-rich mRNA sequences enriched near transcription start sites. Unexpectedly, loss of KAT5–RNA interactions during acute transcriptional inhibition triggers rapid and pronounced promoter hyperacetylation in a KAT5-dependent manner. Biochemical and structural analyses reveal that RNA engages a regulatory RNA-binding region within the HAT domain, sterically blocking substrate access to the catalytic pocket and thereby suppressing KAT5 acetyltransferase activity.