Regulation and Function of Endocrine-Specific Splicing Programs in Pancreas and their Role in Diabetes

Projektbeschreibung

Posttranskriptionelle Regulierung der Zellspezialisierung in der Bauchspeicheldrüse

Die Regulierung der Genexpression findet auf epigenetischer, transkriptioneller und translationaler Ebene statt. Das alternative Spleißen ist ein posttranskriptioneller molekularer Mechanismus, der die Erzeugung mehrerer mRNA-Transkripte aus einem einzelnen Gen ermöglicht. Das wird durch die Kombination alternativer Exons erreicht, die zu unterschiedlichen reifen mRNA sowie unterschiedlichen Proteinen führt und so die Vielfalt ausbaut. Das EU-finanzierte Projekt ePANC-SPLICE untersucht die Rolle des alternativen Spleißens bei der Spezifizierung und Differenzierung verschiedener Linien von Bauchspeicheldrüsenzellen. Die Ergebnisse werden das Wissen über das Aufkommen von Betazellen der Bauchspeicheldrüse, die Insulin absondern, und die Pathophysiologie von Diabetes ausweiten.

Ziel

Pancreatic beta cells are highly specialized cells that play a key role in maintaining glucose homeostasis by secreting insulin. Dysfunction or loss of beta cells results in diabetes, a worldwide growing epidemic. Extensive research has started to uncover the signals and transcriptional networks that control specification, differentiation and maturity of the different pancreatic cell lineages, and in particular of beta cells. However, posttranscriptional regulation during pancreas development has remained mostly unexplored. Alternative splicing (AS) is the main posttranscriptional mechanism that generates transcriptomic and proteomic diversity, playing essential roles in cell specification and functional specialization. My previous data suggest that beta cells activate neuron-related splicing programs involved in the regulation of insulin secretion. Moreover, pro-inflammatory cytokines (mediators of beta cell failure in type 1 diabetes) affect the splicing of signaling and pro-apoptotic genes that determine beta cell survival. However, the presence of beta- or endocrine-specific splicing programs and their role in diabetes remains to be clarified. In this project, we will investigate the regulation and function of endocrine-specific alternative exons. I will combine comparative transcriptomics, biochemical and functional studies, iPCS reprogramming and zebrafish knock-outs to: (i) comprehensively identify endocrine-AS exons, and study their regulation during beta cell differentiation and pancreas development; (ii) probe the phenotypic impact of endocrine-AS programs on beta cell differentiation and function; and (iii) Investigate the role of ENDO-AS exons in remodeling transcriptional and signaling networks involved in diabetes. We foresee that this project will provide new insights into beta cell pathophysiology and generate valuable knowledge for the development of splicing-modulating therapies and disease biomarkers.