Huang Yanlan, Liu Yuxuan, Pu Mingyi, Zhang Yuli, Cao Qiang, Li Senru, Wei Yuanjie, Hou Linlin
School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, 518107, People's Republic of China.
Helmholtz Centre for Infection Research (HZI), Helmholtz Institute for RNA-Based Infection Research (HIRI), Würzburg, Germany.
Cell Biosci. 2024 Aug 19;14(1):102. doi: 10.1186/s13578-024-01284-8.
SOX2 is a determinant transcription factor that governs the balance between stemness and differentiation by influencing transcription and splicing programs. The role of SOX2 is intricately shaped by its interactions with specific partners. In the interactome of SOX2 in mouse embryonic stem cells (mESCs), there is a cohort of heterogeneous nuclear ribonucleoproteins (hnRNPs) that contributes to multiple facets of gene expression regulation. However, the cross-talk between hnRNPs and SOX2 in gene expression regulation remains unclear.
Here we demonstrate the indispensable role of the co-existence of SOX2 and heterogeneous nuclear ribonucleoprotein K (hnRNPK) in the maintenance of pluripotency in mESCs. While hnRNPK directly interacts with the SOX2-HMG DNA-binding domain and induces the collapse of the transcriptional repressor 7SK small nuclear ribonucleoprotein (7SK snRNP), hnRNPK does not influence SOX2-mediated transcription, either by modulating the interaction between SOX2 and its target cis-regulatory elements or by facilitating transcription elongation as indicated by the RNA-seq analysis. Notably, hnRNPK enhances the interaction of SOX2 with target pre-mRNAs and collaborates with SOX2 in regulating the alternative splicing of a subset of pluripotency genes.
These data reveal that SOX2 and hnRNPK have a direct protein-protein interaction, and shed light on the molecular mechanisms by which hnRNPK collaborates with SOX2 in alternative splicing in mESCs.
SOX2是一种决定性转录因子，通过影响转录和剪接程序来控制干性与分化之间的平衡。SOX2的作用是由其与特定伙伴的相互作用复杂地塑造的。在小鼠胚胎干细胞（mESCs）中SOX2的相互作用组中，有一群异质核糖核蛋白（hnRNPs），它们有助于基因表达调控的多个方面。然而，hnRNPs与SOX2在基因表达调控中的相互作用仍不清楚。
在这里，我们证明了SOX2与异质核糖核蛋白K（hnRNPK）共存对维持mESCs多能性的不可或缺的作用。虽然hnRNPK直接与SOX2-HMG DNA结合域相互作用并诱导转录抑制因子7SK小核核糖核蛋白（7SK snRNP）的解体，但如RNA测序分析所示，hnRNPK既不通过调节SOX2与其靶顺式调控元件之间的相互作用，也不通过促进转录延伸来影响SOX2介导的转录。值得注意的是，hnRNPK增强了SOX2与靶前体mRNA的相互作用，并与SOX2协同调节一部分多能性基因的可变剪接。
这些数据揭示了SOX2和hnRNPK存在直接的蛋白质-蛋白质相互作用，并阐明了hnRNPK与SOX2在mESCs可变剪接中协同作用的分子机制。
