Structural basis for site-specific histone H3 acetylation-dependent regulation of RNAPII transcription through nucleosomes

Abstract

Acetylation of histone H3 regulates chromatin dynamics and transcription, but how specific acetylation sites affect RNA polymerase II (RNAPII) transcription through nucleosomes remains unclear. Here, we found that H3 acetylation at Lys56 and Lys122 markedly enhances RNAPII transcription through nucleosomes, whereas acetylation at Lys64 has little effect. To elucidate the structural basis for these functional differences, we determined cryo-electron microscopy (cryo-EM) structures of nucleosomes bearing site-specific acetylation at H3K56, H3K64, or H3K122. The cryo-EM structures revealed that H3K56ac and H3K122ac locally weaken histone-DNA interactions at the DNA entry/exit region and near the dyad, respectively, while H3K64ac induces no detectable structural changes. These structural differences correlate with the observed transcriptional outcomes, indicating that acetylation at H3K56 and H3K122, but not H3K64, alleviates the nucleosomal barrier to RNAPII progression. Our findings provide direct structural evidence that specific acetylations within the histone fold domain of H3 finetune nucleosome dynamics to facilitate RNAPII transcription.