Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Nat Struct Mol Biol. 2012 Oct;19(10):1044-52. doi: 10.1038/nsmb.2377. Epub 2012 Sep 16.
Most human genes produce multiple splicing isoforms with distinct functions. To systematically understand splicing regulation, we conducted an unbiased screen and identified >100 intronic splicing enhancers (ISEs), clustered by sequence similarity. All ISEs functioned in multiple cell types and in heterologous introns, and patterns of distribution and conservation across pre-mRNA regions were similar to those of exonic splicing silencers. Consistently, all ISEs inhibited use of splice sites from exons. Putative trans-factors of each ISE group were identified and validated. Five distinct groups were recognized by hnRNP H and hnRNP F, whose C-terminal domains were sufficient to render context-dependent activities of ISEs. The sixth group was controlled by factors that either activate or suppress splicing. We provide a comprehensive picture of general ISE activities and suggest new models of how single elements can function oppositely, depending on locations and binding factors.
大多数人类基因产生具有不同功能的多种剪接异构体。为了系统地理解剪接调控，我们进行了一项无偏筛选，鉴定出了>100 个序列相似性聚类的内含子剪接增强子（ISE）。所有 ISE 在多种细胞类型和异源内含子中均起作用，其在 pre-mRNA 区域的分布和保守模式与外显子剪接沉默子相似。一致地，所有 ISE 均抑制来自外显子的剪接位点的使用。每个 ISE 组的推定反式因子被鉴定和验证。通过 hnRNP H 和 hnRNP F 识别出五个不同的组，其 C 端结构域足以赋予 ISE 依赖上下文的活性。第六组由激活或抑制剪接的因子控制。我们提供了一般 ISE 活性的全面描述，并提出了新的模型，说明单个元件如何根据位置和结合因子而具有相反的功能。
