SETD2 contributes to gene expression by marking gene bodies with H3K36me3, which is thought to assist in the concentration of transcription machinery at the small portion of the coding genome. Despite extensive genome-wide data revealing the precise localization of H3K36me3 over gene bodies, the physical basis for the accumulation, maintenance, and sharp borders of H3K36me3 over these sites remains rudimentary. Here we propose a model of H3K36me3 marking based on stochastic transcription-dependent placement and transcription-independent spreading. Our analysis of the spatial distributions and dynamic features of these marks indicates that transcription-dependent placement dominates the establishment of H3K36me3 domains compared to transcription-independent spreading processes, and that turnover of H3K36me3 limits its capacity for epigenetic memory. By adding additional terms for asymmetric histone turnover occurring at transcription start sites, our model provides a remarkably accurate representation of H3K36me3 levels and dynamics over gene bodies. Furthermore, we validate our findings by revealing that loss of SPT6 impairs the transcription-coupled activity of the SETD2:IWS1:SPT6 ternary complex, thereby reducing the tight correlation between transcription and H3K36me3 levels at gene bodies.

Dynamics of transcription-dependent H3K36me3 marking by the SETD2:IWS1:SPT6 ternary complex