Epigenomic control of RNA splicing

描述(由申请人提供)：本项目的中心目标是阐明表观遗传学和染色质状态在RNA剪接调控中的作用。真核细胞产生惊人的调控多样性，因此从有限的一组基因中产生极其复杂的表型。选择性的前mRNA剪接通过从单个基因产生多个RNA亚型，在创造这种调控多样性方面发挥了重要作用。传统上，剪接被认为是一个转录后的过程，剪接调控的研究主要集中在顺式剪接调控元件的作用以及它们与规范的RNA结合剪接因子的相互作用。然而，最近对真核生物表观基因组和转录体的研究揭示了由染色质状态和表观遗传标记形成的剪接调控的惊人复杂图景。外显子的特征是核小体定位、DNA甲基化和某些组蛋白修饰水平增加。当新生RNA与染色质连接时，许多内含子被共转录剪接，转录延伸率或表观遗传标记的变化可以影响外显子剪接模式。尽管有这些令人兴奋的发现，但许多关于剪接的表观遗传调控的问题仍然没有解决。我们建议利用表观基因组路线图项目产生的广泛而深入的表观基因组和转录组数据，系统地研究染色质和RNA剪接的表观遗传调控。通过将不同细胞类型的转录组图谱与表观基因组图谱相关联，我们的目标是解决关于共转录和转录后RNA剪接的表观遗传调控的一系列重要问题。在三个目标中，我们将研究不同组织和细胞类型中的表观基因组-剪接相关性(目标1)，确定与剪接相关的染色质组合状态和远程相互作用(目标2)，并阐明表观遗传决定因素如何影响染色质相关剪接(目标3)。所提出的研究将极大地促进我们对剪接调控的理解，以及表观遗传信号如何影响正常和疾病细胞中的选择性剪接。此外，通过拟议的工作，我们将开发新的计算方法，将表观基因组签名与RNA剪接模式联系起来。我们预计这些工具将对研究不同生物系统中的表观基因组和转录组调控的研究人员产生广泛的兴趣和作用。

DESCRIPTION (provided by applicant): The central objective of this project is to elucidate the roles of epigenetics and chromatin states in RNA splicing regulation. Eukaryotic cells generate astonishing regulatory diversity and as a consequence exceedingly complex phenotypes from a finite set of genes. Alternative pre-mRNA splicing plays an essential role in creating this regulatory diversity by generating multiple RNA isoforms from a single gene. Traditionally, splicing was considered as a "post-transcriptional" process, and studies of splicing regulation have largely focused on the roles of cis splicing regulatory elements and their interactions with canonical RNA-binding splicing factors. However, recent studies of eukaryotic epigenomes and transcriptomes have revealed a surprisingly complex picture of splicing regulation shaped by chromatin states and epigenetic marks. Exons are characterized by increased levels of nucleosome positioning, DNA methylation, and certain histone modifications. Many introns are spliced co-transcriptionally when the nascent RNAs are tethered to the chromatin, and changes in the transcription elongation rate or epigenetic marks can influence exon splicing patterns. Despite these exciting findings, many questions about epigenetic regulation of splicing remain unresolved. We propose to systematically investigate chromatin and epigenetic regulation of RNA splicing, by taking advantage of the broad and deep epigenome and transcriptome data generated by the Epigenome Roadmap project. By correlating transcriptome profiles to epigenome profiles across diverse cell types, we aim to address a series of important questions regarding epigenetic regulation of co-transcriptional and post-transcriptional RNA splicing. In three aims, we will investigate epigenome-splicing correlation in diverse tissues and cell types (Aim 1), identify combinatorial chromatin states and long-range interactions associated with splicing (Aim 2), and elucidate how epigenetic determinants affect chromatin-associated splicing (Aim 3). The proposed studies will significantly advance our understanding of splicing regulation, and how epigenetic signals influence alternative splicing in normal and diseased cells. In addition, through the proposed work we will develop novel computational methods for linking epigenome signatures to RNA splicing patterns. We anticipate that these tools will be of broad interest and utility to researchers studying epigenome and transcriptome regulation in diverse biological systems.