Institute of Human Genetics, UMR9002 CNRS-University of Montpellier, 34000, Montpellier, France.
Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Nat Commun. 2021 Jan 29;12(1):682. doi: 10.1038/s41467-021-20979-x.
Alternative splicing relies on the combinatorial recruitment of splicing regulators to specific RNA binding sites. Chromatin has been shown to impact this recruitment. However, a limited number of histone marks have been studied at a global level. In this work, a machine learning approach, applied to extensive epigenomics datasets in human H1 embryonic stem cells and IMR90 foetal fibroblasts, has identified eleven chromatin modifications that differentially mark alternatively spliced exons depending on the level of exon inclusion. These marks act in a combinatorial and position-dependent way, creating characteristic splicing-associated chromatin signatures (SACS). In support of a functional role for SACS in coordinating splicing regulation, changes in the alternative splicing of SACS-marked exons between ten different cell lines correlate with changes in SACS enrichment levels and recruitment of the splicing regulators predicted by RNA motif search analysis. We propose the dynamic nature of chromatin modifications as a mechanism to rapidly fine-tune alternative splicing when necessary.
可变剪接依赖于剪接调控因子组合募集到特定的 RNA 结合位点。染色质已被证明会影响这种募集。然而，在全局水平上研究的组蛋白标记物数量有限。在这项工作中，机器学习方法应用于人类 H1 胚胎干细胞和 IMR90 胎儿成纤维细胞中的广泛表观基因组数据集，鉴定出十一种染色质修饰，根据外显子包含的水平，这些修饰可区分可变剪接的外显子。这些标记物以组合和位置依赖的方式发挥作用，形成特征性的剪接相关染色质特征 (SACS)。为了支持 SACS 在协调剪接调控中的功能作用，十个不同细胞系之间 SACS 标记外显子的可变剪接变化与 SACS 富集水平的变化以及 RNA 基序搜索分析预测的剪接调控因子的募集相关。我们提出染色质修饰的动态性质是在必要时快速微调可变剪接的一种机制。
