SETD2 contributes to PAF1C interactions with the elongating RNA Pol II and is required for neuronal differentiation [ChIP-Seq]

Chromatin modifications are relevant for mammalian development, and their aberrant deposition is associated with human disease. While the mechanisms that deposit and remove these modifications have been largely elucidated, their role in regulating gene activity during cellular differentiation has yet to be completely understood. By differentiating a panel of mouse embryonic stem cells lacking major chromatin regulators towards neuronal cells, we identified their requirement at different stages of cellular differentiation. We show that the H3K36me3 methyltransferase SETD2 is important for the establishment of neuronal gene expression during late stages of differentiation but is dispensable once the cells have fully differentiated. While we don’t find evidence for a requirement of the histone methyltransferase activity in this process, we identify an indirect role of SETD2 in mediating interactions between the PAF1 complex and the elongating RNA Pol II, which could be required for optimal transcriptional processivity of neuronal genes.