TRANSCRIPTOME 2002: From Functional Genomics to Systems
Molecular Mechanisms of Pre-mRNA Splicing Regulation
Juan Valcárcel, Gene Expression Programme, European Molecular Biology Laboratory, Heidelberg, GERMANY
At least 45-60 % of human genes produce primary transcripts that can be alternatively spliced to generate up to thousands of potential mRNAs and protein isoforms, thus significantly expanding the informational content of the genome. Alternative splicing can originate proteins with diverse, even opposite functions, and has the capacity to spawn combinatorial complexity that can serve to establish cellular networks. The process is often subverted in disease, and up to 40% of genetic defects can be associated with incorrect RNA processing. Despite the prevalence of alternative splicing and the versatility it provides for the regulation of gene expression, the molecular mechanisms involved in the use of different splice sites during cell differentiation, development and disease are poorly understood.
Work in my lab focuses on three areas: To study in detail the mechanisms used by tissue-specific factors to promote or repress particular splice sites, with the goal of understanding which steps of the splicing process are targets of regulation. Work has focused on a Drosophila RNA binding protein, Sex-lethal, that is expressed exclusively in female flies and induces female-specific patterns of alternative splicing. While some alternative splicing events are regulated by Sex-lethal at the earliest steps of splice site recognition, recent results indicate that it can also regulate the very last step of the splicing process: the joining of the exons and intron release. This observation opens novel mechanistic possibilities for splicing regulation. Similar molecular events are also at the basis of cryptic splice site activation in at least one form of human beta-thalassemia. To understand how ubiquitous splicing factors can be activated to modulate alternative splicing during the process of programmed cell death. Work focuses on a signal transduction cascade that targets the splicing factor TIA-1 and modulates alternative splicing of the Fas receptor in T cell immune responses. Some elements of this cascade appear to be altered in Autoimmune Lymphoproliferative Syndromes. To gain insights into the molecular logic behind the establishment of post-transcriptional regulatory programs. We are using bioinformatic and microarray analyses to identify novel genes whose alternative splicing is controlled by specific splicing regulators.
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