Journal Article

Intronic splicing enhancers, cognate splicing factors and context-dependent regulation rules

Wang, Yang, Xiao, Xinshu, Ma, Meng, Wang, Zefeng

2012

Overview

A systematic, unbiased screen for general intronic splicing enhancers (ISEs) identified >100 ISEs that promote intron splicing but inhibit splicing in exons. Putative trans -factors for clusters of ISEs were identified, validated and were found to control ISE activity in a context-dependent manner. Altogether, the data provide a comprehensive picture of how ISEs function depending on their location and cognate trans -factors. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/337/1645/1946 / Biochemistry / Biological Microscopy / Biomedical and Life Sciences / Cell Line / Enhancer Elements, Genetic / Gene Expression Regulation / Genetic engineering / Genetics / Heterogeneous-Nuclear Ribonucleoprotein Group F-H - genetics / Heterogeneous-Nuclear Ribonucleoprotein Group F-H - metabolism / Humans / Introns / Life Sciences / Membrane Biology / Methods / Molecular biology / Nucleotide Motifs / Promoters (Genetics) / Properties / Protein Structure / Protein Structure, Tertiary / Reproducibility of Results / resource / RNA Precursors - genetics / RNA sequencing / RNA Splicing / RNA-Binding Proteins - genetics / RNA-Binding Proteins - metabolism