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FRIMEDBIO-Fri med.,helse,biol

Deconvoluting disease-associated genetic variants in noncoding RNA genes using functional genomics

Alternative title: Avkoding av sykdomsassosierte genetiske varianter i ikke-kodende RNA-gener ved bruk av funksjonell genomikk

Awarded: NOK 4.3 mill.

Sequencing the human genome in 2001 has been praised as one of the most important achievement of human kind. Since then, researchers were able to identify function of genes and relate genes with diseases. This has led to life-saving blockbuster drugs and hence, treatment possibilities for numerous diseases. However, in recent years it has become clear that our DNA harbors another, understudied gene entity and there are in fact many more of those genes than the ones studied thus far. Today, we know of around 25'000 "noncoding" genes with currently enigmatic functions and unknown involvement in human diseases. We will now test the importance of all those noncoding genes in common human diseases (Obesity, Cardiovascular diseases, Neurological disorders, etc) by assessing mutations in noncoding genes. Due to limited large-scale data this has not been possible until today. We will dissect function of enigmatic, noncoding genes in >50 human tissues. Moreover, we will go beyond association of noncoding genes and diseases and causally assess diseases-associated variants in human stem cell and organoid models by employing state-of-the-art genome editing tools. In this process, we will also tackle the fundamental question of molecular biology whether, and how noncoding mutations affect its RNA product. Lastly, efficacy of noncoding gene therapy will be tested to reverse disease characteristics. In summary, recently emerging big data sets finally allow the in-depth, multi-tissue characterization of mutations in noncoding genes. Our proposed research project will take advantage of this and combine computational genetic analyses with molecular assays with the goal to not only identify novel disease-associated, noncoding genes but also to develop curative treatment options against those diseases.

Emerging RNA-based therapies permit exploitation of vast numbers (>30'000) of noncoding RNA transcripts as putative drug targets. However, function of most noncoding RNA genes is currently unknown due to the lack of comprehensive, genome-wide interrogation of these enigmatic genes. Therefore, we will take the first step and rank ncRNA genes by their genetic importance for human health and disease. We will test the provocative hypothesis that mutations in noncoding RNA exons disrupt RNA processing and therefore, have a profound impact on human health. This hypothesis is firmly rooted in the expanding field of noncoding DNA variants and RNA therapeutics. Capitalizing on our expertise in genomics and molecular assays we will identify disease-associated mutations within noncoding exons and characterize their effect on RNA transcripts in 49 human tissues. Direct candidate testing of candidate variants will be performed using state-of-the-art technologies, such as CRISPR DNA editing tools in human iPSCs prior to differentiation to disease-relevant cell types where aberrant RNA expression was observed. We will assess effects of DNA edits (mimicking disease-associated SNPs) on RNA processing, while measuring disease-associated phenotypes in parallel. Putative mechanisms such as polymerase II detachment and nonsense-mediated decay (NMD) will be systematically explored. Reconstitution experiments will finally serve as proof-of-concept and nominate RNA-based therapy as a curative strategy. This multifaceted approach will allow us to characterize the impact of noncoding RNA mutations, examine the molecular basis of mutations in RNA genes, and to identify RNA drug targets, each providing an entirely new framework within which to understand the untapped potential of noncoding RNA genes. Our transformative study will take advantage of recently emerging databases connecting RNA levels to genotypes in bigger human cohorts as well as innovative tools to study human genetic variants.

Funding scheme:

FRIMEDBIO-Fri med.,helse,biol