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Pre-mRNA splicing is a fundamental step in mRNA maturation and its discovery in 1977 revolutionized our understanding of gene expression. This collection includes reviews and research articles from across the Nature group of journals to showcase the latest advances in splicing research and the emerging understanding of how splicing regulates gene expression, and through it cell fate, development and physiology. The articles focus on topics that include alternative splicing, the architecture and function of spliceosome complexes, the coordination of splicing with other processes such as transcription and mRNA decay, and splicing-related diseases and therapeutics.
Atomic-resolution structures have recently been obtained for the intact spliceosome at different stages of the splicing cycle. These structural data have proved that the spliceosome is a protein-directed metalloribozyme and have increased our understanding of pre-mRNA splicing mechanisms, explaining a large body of existing genetic and biochemical data.
Pre-mRNA splicing occurs on nascent RNA, which is attached to chromatin by RNA polymerase II. Much splicing occurs co-transcriptionally, and the spatial and temporal coordination of the two processes is tightly coordinated with other mRNA-processing events.
Alternative splicing expands the complexity of the proteome by generating multiple transcript isoforms from a single gene. Numerous alternative splicing events occur during cell differentiation and tissue maturation, suggesting that alternative splicing supports proper development. Recent studies shed light on how alternative splicing and its coordination contribute to organ development and tissue homeostasis.
This Review discusses the current genetic and functional links between dysregulated and/or mutated RNA splicing factors and cancer, as well as the therapeutic opportunities presented by alterations in alternative splicing in cancer.
Complex and intricate RNA splicing mechanisms are crucial for gene regulation and for maximizing proteomic diversity. This Review discusses how alterations to splicing mechanisms — such as mutations in pre-mRNAs, or mutations and dysregulation of core spliceosome proteins and other RNA-binding proteins — results in diverse molecular consequences and various diseases. Opportunities for therapeutic correction of these defects are also explored.
Genetic variants can produce phenotypic traits through effects on RNA processing, including effects on pre-mRNA splicing, 3′ end formation, and RNA stability, localization, structure and translation efficiency.
Although non-coding RNAs have roles in transcription and chromatin function, nascent pre-mRNA is usually considered to be passive during these processes. Recently identified interactions between nascent pre-mRNAs and regulatory proteins suggest that both types of RNA regulate transcription and chromatin function.
Circular RNAs (circRNAs) are pervasively expressed in eukaryotic genomes, representing the major transcript isoform for many genes. In this article, the authors review sources of experimental and bioinformatic biases that complicate the accurate discovery of circRNAs and discuss statistical approaches used by published algorithms to address these biases.
Patterns of splicing are frequently altered in cancer, and genes that encode splicing regulatory factors are often mutated. Thus, recent strategies have emerged to target splicing alterations in cancer, which are reviewed here.
Advances in transcriptomics and analysis have identified thousands of previously unknown non-canonical splicing events. In this Review, the authors discuss the mechanisms and functions of these events and their roles in a variety of diseases. They explain how non-canonical splicing mechanisms can be targeted or exploited for therapeutic strategies.
Alternative splicing is a key regulatory step in gene expression that affects all aspects of neuronal development and function. In this Review, Vuong and colleagues survey recent genetic studies of splicing regulators and the diverse parts they play in the mammalian nervous system.
Circular RNAs (circRNAs) are produced from precursor RNA back-splicing. Recent findings reveal the complexity of the biogenesis of circRNAs and their cell type-specific expression. They also show that circRNAs can shape eukaryotic transcriptomes by sequestering microRNAs and by regulating transcription and interfering with splicing.