Beta-splicenet · ALTERNATIVE SPLICING NETWORKS IN PANCREATIC BETA CELLS
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2015-06-01 → 2017-05-31
- EU contribution
- €160,800
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
ALTERNATIVE SPLICING NETWORKS IN PANCREATIC BETA CELLS
The project Beta-splicenet focused in studying the role of RNA alternative splicing (AS), a complex mechanism of gene regulation, in insulin-producing pancreatic beta cells. Our goal was to understand how AS regulates beta cell function and survival, and how alterations in this process may contribute to the development of type 1 diabetes (T1D). T1D results from the interaction between predisposing genes and environmental factors, triggering an autoimmune attack against pancreatic beta cells that leads to their progressive loss due to cell death. However, the molecular mechanisms and signals promoting beta cell dysfunction and loss are poorly understood. AS allows single genes to produce multiple protein variants with different functions, playing a critical role in the control of cell-specific functions. In this project, we used a systems biology approach combining next generation sequencing, bioinformatics and functional studies in beta cell models, to unveil splicing networks that regulate key beta cell functions that may be altered during the development of T1D. Moreover, we also explored the modulation of AS by small molecules as a novel therapeutic approach to prevent beta cell loss. During this project we identified several splicing regulators and their associated RNA networks that modulate the activity of key pathways and processes for the survival and secretory function of beta cells. Moreover, we showed that some of these splicing networks are dysregulated by inflammation or diabetes susceptibility genes, contributing to the general beta cell demise that occurs during the development of the disease.
Data: CORDIS, © European Union
Project objective
Type 1 diabetes (T1D) is a chronic autoimmune disease in which pancreatic beta cells are killed by infiltrating immune cells and by cytokines released by these cells. The mechanisms by which autoimmunity is triggered and aggravated in T1D and the nature of the intracellular signals that decide beta cell fate between survival or death remain to be clarified. Alternative splicing (AS) is a complex mechanism of gene expression regulation and a potent generator of proteome diversity. It provides cells with an exquisite capacity to rapidly modify their transcriptome and proteome in response to intra and extracellular cues. AS affects more than 90% of human genes and has a major impact in many cellular processes, including cell survival and generation of new antigenic epitopes. There is a growing interest in the role of AS in autoimmune diseases but nearly nothing is known on its role in beta cells and diabetes. Recent findings by the host group indicate that pro-inflammatory cytokines change the expression of >30 RNA-binding proteins (RBPs) and modify AS of >3000 genes in human beta cells. Importantly, the host group has discovered that the diabetes candidate gene GLIS3 affects beta cell apoptosis by regulating the splicing of the pro-apoptotic BH3-only protein Bim. These findings suggest that AS plays an important role in the regulation of beta cell dysfunction and death by mechanisms that remain to be clarified. We hypothesise that pro-inflammatory signals activate splicing networks contributing to beta cell functional lost and death. We propose in the present project a systems biology approach that will combine RNA-seq, network inference and analysis of individual RBPs to characterize and validate inflammation-activated splicing networks in beta cells. The ultimate goal is to identify key splicing networks and mRNA splice variants that will be targeted by splicing-modulation molecules as a novel therapeutic strategy to prevent progressive beta cell loss in T1D.
Original text from CORDIS.
Participants
- UNIVERSITE LIBRE DE BRUXELLES · Bruxelles / BrusselCoordinatorBelgium
Links
Data: CORDIS, © European Union