GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE345nnn/GSE345461/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE345461GEOGSEfalseRNA fine-tunes KAT5 activity to shape chromatin acetylation during active transcription [RNA-Seq]KAT5 is a prominent histone acetyltransferase that deposits acetylation on histone H4 to regulate transcription, genome stability, and cell fate decisions. 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. Our findings uncover nascent RNA as a reversible allosteric inhibitor of KAT5, revealing an RNA-directed feedback mechanism that modulates promoter acetylation and transcriptional output.2026/09/22GSE345461GSM10004960GSM10004958GSM10004959GSM10004954GSM10004955GSM10004956GSM10004957GSM10004961GSM10004962GSM10004952GSM10004963GSM1000495334295345461Homo sapiens