The H3K36me3 methyltransferase SETD2 contributes to PAF1C interactions with RNA Pol II and is required for neuronal differentiation

Chromatin modifications are essential for mammalian development, and their aberrant deposition is associated with human disease. While the mechanisms that deposit and remove histone modifications have been largely elucidated, their roles in regulating gene activity during cellular differentiation are yet to be fully understood. Here, we performed a deletion screen to identify stage-specific requirements of chromatin regulators during neuronal differentiation of mouse embryonic stem cells. We show that the H3K36me3 methyltransferase SETD2 is required for the establishment of neuronal gene expression during late stages of differentiation but is dispensable in mature neurons. Notably, this function is independent of its histone methyltransferase activity. Instead, SETD2 promotes interactions between the PAF1 complex and elongating RNA Pol II, suggesting a role in supporting efficient transcription of neuronal genes.