Heterogeneous ribonucleoproteins (hnRNPs) are RNA binding molecules that are involved in key processes such as RNA splicing and transcription. One such hnRNP protein, hnRNP L, regulates alternative splicing (AS) by binding to pre-mRNA transcripts. However, it is unclear what factors contribute to hnRNP L-regulated AS events. Using proteomic approaches, we identified several key factors that co-purify with hnRNP L. We demonstrate that one such factor, the histone methyltransferase SETD2, specifically interacts with hnRNP L in vitro and in vivo.This interaction occurs through a previously uncharacterized domain in SETD2, the SETD2-hnRNP L Interaction (SHI) domain, the deletion of which, leads to a reduced H3K36me3 deposition. Functionally, SETD2 regulates a subset of hnRNP L-targeted AS events. Our findings demonstrate that SETD2 by interacting with Pol II as well as hnRNP L, can mediate the crosstalk between the transcription and the splicing machinery.Alternative splicing (AS) of pre-mRNA is a crucial process that enables cells to synthesize different protein isoforms from the same gene (Kelemen et al., 2013). It occurs by the rearrangement of intron and exon elements that are joined by protein-RNA complexes known as the spliceosome to determine the mRNA coding sequence. It is estimated that 95% of the human genes undergo AS and this gives rise to the protein diversity needed for the varied cell types and functions from a limited set of genes (Pan et al., 2008)(Wang et al., 2008. AS functions in critical biological processes including cell growth, cell death, pluripotency, cell differentiation, development, and circadian rhythms (Barbosa-Morais et al., 2012)(Kalsotra and Cooper, 2011)(McGlincy et al., 2012.It is clear now that pre-mRNA splicing is coupled to transcription. Such coupling permits the sequential recognition of emerging splicing signals by the splicing factors (Oesterreich et al., 2011). Two models have been proposed to explain this coupling. The ''kinetic model'' proposes that changes in the rate of Pol II transcription influence the splice site selection process and hence, AS (Drahansky et al., 2016)(Schor et al., 2013. According to the ''recruitment model'', Pol II plays a central role in recruiting specific splicing regulators for co-transcriptional regulation of AS (Drahansky et al., 2016)(Schor et al., 2013).An example of specific splicing regulators that are important in pre-mRNA processing and could be players in the ''recruitment model'' are the RNA-binding heterogeneous nuclear ribonucleoproteins (hnRNPs). hnRNPs bind to splice sites in the pre-mRNA and regulate splicing (Lee et al., 2015). The role of hnRNPs in regulating gene expression is of increasing interest in disease research. The expression level of hnRNPs is altered in many types of cancer, suggesting their role in tumorigenesis (Han et al., 2013). In addition to cancer, many hnRNPs have also been linked to neurodegenerative diseases, such as spinal muscular atrophy, amyotrophic lateral sclerosis, Alzheimer's disease, and frontote...
