Stowers Institute for Medical Research, Kansas City, MO, USA.
Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA.
Nat Commun. 2021 Mar 4;12(1):1443. doi: 10.1038/s41467-021-21663-w.
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.
异质核糖核蛋白（hnRNPs）是一种 RNA 结合分子，参与 RNA 剪接和转录等关键过程。hnRNP 蛋白家族中的一员 hnRNP L 通过与 pre-mRNA 转录本结合来调节可变剪接（AS）。然而，尚不清楚哪些因素导致 hnRNP L 调节的 AS 事件。我们使用蛋白质组学方法鉴定了与 hnRNP L 共纯化的几个关键因子。我们证明，其中一个因子，组蛋白甲基转移酶 SETD2，在体外和体内均与 hnRNP L 特异性相互作用。这种相互作用发生在 SETD2 中一个以前未被表征的结构域，即 SETD2-hnRNP 相互作用（SHI）结构域，该结构域缺失会导致 H3K36me3 沉积减少。功能上，SETD2 调节 hnRNP L 靶向的 AS 事件的一部分。我们的研究结果表明，SETD2 通过与 Pol II 以及 hnRNP L 相互作用，可以介导转录和剪接机制之间的串扰。
