Linking H3K36me3 to transcriptional dynamics

Abstract

Genes are transcribed in bursts as they fluctuate between on and off states, in a process modulated by histone modifications. The mammalian histone methyltransferase SETD2 is solely responsible for depositing H3K36 trimethylation, which recruits histone deacetylases and regulates histone occupancy. Nucleosomes are known to act as a barrier to transcription elongation and have been observed to impact elongation rate. H3K36me3 has been associated with long pausing sites in gene bodies and is implicated in reducing speed of successive RNA polymerase II. However, the role of SETD2 and H3K36me3 in transcriptional dynamics are unknown. Here we show upon SETD2 knockout and H3K36me3 depletion in murine C2C12 myoblast cells that overall gene expression is reduced and splicing fidelity affected, as 5' mutually exclusive exons are favoured over 3' ones. Furthermore, transcriptional burst size is reduced, while bursting frequency increased. A simple mathematical model suggests that the observed changes in transcriptional dynamics can be explained by less stringently controlled polymerase pausing in the gene bodies of H3K36me3 depleted cells.