Aarhus Universitets segl

Søren Lykke-Andersen

We pursue two different avenues of research in applied and basic RNA biology, respectively.

Applied Biology: RNA Therapeutics

We aim to develop customizable nucleotide-based drugs for haploinsufficiency disorders, which are diseases caused by loss-of-function of one autosomal gene copy, resulting in a halving of the protein amount. There are ~350 verified haploinsufficiencies, including many severe ailments like cancer and neurodevelopmental disorders. With most lacking treatment options, these disorders represent a significant unmet medical need, and therapeutic interventions that increase functional protein levels are in high demand. Our approaches focus on targeting the mRNA with engineered RNAs to boost protein levels from the healthy allele. We are particularly interested in the development of platform technologies, where the same method can be designed for any haploinsufficiency, and the specific mutation is irrelevant.

Basic Biology: small nucleolar RNAs

Small nucleolar RNAs (snoRNAs) are ancient and abundant regulatory RNAs present in all archaea and eukaryotes. They are essential for producing optimally functional ribosomes. snoRNAs form catalytic ribonucleoprotein particles (snoRNPs) by partnering with proteins, which act on target RNAs. There are two main types of snoRNPs: box C/D and box H/ACA subtypes, which catalyze 2’-O-methylation and pseudouridylation of targeted nucleotides, respectively.

Some specialized subsets of box C/D snoRNPs do not introduce rRNA modifications; instead, they direct specific endocleavage and folding events during rRNA processing. Recent findings also suggest that box C/D snoRNPs play a direct role in controlling rRNA transcription by methylating histones in the nucleolus.

After establishing key aspects of the intricate regulation governing the expression of box C/D snoRNAs and their associated protein partners in human cells, our current objective is to understand the mechanistic details of how this regulation influences fundamental cellular processes. Preliminary data strongly indicate an unexplored central role in ribosome metabolism, which has significant implications for cellular homeostasis