The methyltransferase SETD2 couples transcription and splicing by engaging mRNA processing factors through its SHI domain

Abstract Heterogeneous ribonucleoproteins (hnRNPs) are RNA binding molecules that involved in key processes such as splicing and transcription. One hnRNP protein, L, regulates alternative (AS) by to pre-mRNA transcripts. However, it is unclear what factors contribute L-regulated AS events. Using proteomic approaches, we identified several co-purify with L. We demonstrate one factor, the histone methyltransferase SETD2, specifically interacts L vitro vivo. This interaction occurs through a previously uncharacterized domain SETD2-hnRNP Interaction (SHI) domain, deletion of which, leads reduced H3K36me3 deposition. Functionally, SETD2 subset L-targeted Our findings interacting Pol II well can mediate crosstalk between transcription machinery.