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

Saikat Bhattacharya,Laurence Florens,Michaella J Levy,Jerry L Workman,Hua Li,Ning Zhang,Michael P Washburn

doi:10.1038/s41467-021-21663-w

Abstract

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 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.

Highlights

Heterogeneous ribonucleoproteins are RNA binding molecules that are involved in key processes such as RNA splicing and transcription
The ability of SETD2 to bind to the elongating Pol II as well as the splicing factors makes it an ideal candidate to facilitate such a temporal process
Earlier studies aimed to find the RNA-binding motif of Heterogeneous ribonucleoproteins (hnRNPs) L revealed that it binds to CA-rich regions, which are widespread in mRNAs

Summary

Introduction

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. Alternative splicing (AS) of pre-mRNA is a crucial process that enables cells to synthesize different protein isoforms from the same gene[1]. 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). Are involved in AS regulation, which increases the complexity of the process This being the case, it would be logical to expect that hnRNPs would bind to specific target sequences to influence AS

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