Prinicpal Investigator
Research Details
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Project Leaders
Dr. Gabrijela Dumbovic
Goethe University Frankfurt
dumbovic@med.uni-frankfurt.de -
Research Staff
Dr. Anusha Chaudhuri (Postdoc)
chaudhuri@med.uni-frankfurt.de
Dr. Josep Biayna Rodrigues (Postdoc)
Rebeca Cordellini Emidio (PhD student)
cordelliniEmidio@med.uni-frankfurt.de
Anne Birke (PhD student)
Luise-Elektra Keller (PhD student)
l.keller@med.uni-muenchen.de
The function of a lncRNA is determined by its subcellular localization. In contrast to mRNAs, which are typically enriched in the cytoplasm close to the translation machinery, lncRNAs can be found virtually throughout the cell, and therefore can act in a wide range of cellular processes. Intron retention (IR) is a cell type-specific alternative splicing event that generally leads to nuclear retention of the RNA. We and others showed that lncRNAs have significantly higher IR than mRNAs. IR levels are prone to regulation by external stimuli, which can thus affect nuclear RNA compartmentalization. However, the role of IR in regulating lncRNA function and disease initiation/progression is largely unknown. Insufficient oxygen levels (hypoxia) induce significant changes in the functioning of the cardiovascular system, which can lead to cardiovascular diseases. According to our preliminary findings, a considerable portion of cellular RNAs are affected by IR in response to hypoxia and in heart failure, accompanied by changes in their subcellular localization. The identified transcripts regulate important cellular activities, including transcription and intracellular signaling. Therefore, the goal of this project is to identify and determine the functional significance of changes in the nuclear-cytoplasmic localization of lncRNAs initiated by IR as a response to hypoxia and recovery in normoxia. To address this, we will undertake computational and imaging analyses to identify localization changes mediated by IR. In parallel, we will focus on the most promising lncRNA candidates and use molecular, biochemical and genetic approaches to investigate functions and mechanisms of their subcellular localization regulation. Furthermore, we will use “massively parallel RNA assays” for high-throughput dissection of RNA elements regulating IR. Combined, these studies will provide key mechanistic insights into how changes in lncRNA splicing and localization contribute to the hypoxia response and heart disease.
