Structure of histone deacetylase complex Rpd3S bound to nucleosome

Abstract Histone modifications are involved in the regulation of chromatin-based processes, including transcription, DNA replication and repair1–5. Among them, histone acetylation and deacetylation are usually correlated with transcription activation and repression, respectively6. The Set2-Rpd3S pathway maintains hypoacetylation states of actively transcribed chromatin regions to suppress cryptic transcription initiation7–9. During this process, the histone deacetylase (HDAC) complex Rpd3S is recruited to nucleosomes which are methylated at lysine 36 residue of histone H3 (H3K36me) by histone methyltransferase Set27,9. However, how the five unique subunits of Rpd3S are assembled and coordinated to recognize nucleosomal substrates and exert its deacetylation function remains unclear. Here, we report the cryo-electron microscopy (cryo-EM) structure of Saccharomyces cerevisiae Rpd3S deacetylase bound to H3K36me3-modified nucleosome at 3.1 Å resolution. It reveals that Sin3 and Rco1 subunits orchestrate the assembly of the complex and mediate its contact with nucleosome at multiple sites. In addition, the chromodomain (CHD) of Eaf3 subunit recognizes the H3K36me3 marker and contacts both nucleosomal and linker DNA. The structure not only unravels the architecture of the Rpd3S complex, but also sheds light on the structural basis of its nucleosome targeting and function.