Research

The research activities within the NCCR RNA & Disease aim at advancing our understanding of fundamental mechanisms in RNA biology, identifying disease phenotypes related to these mechanisms and developing ideas for novel therapeutic and diagnostic approaches. As a first step towards this goal, we will elucidate the molecular underpinnings of fundamental cellular processes and discover novel pathways. Building on the knowledge gained from our basic research, we explore how these findings can be used to solve medical challenges for both diagnostic and therapeutic applications as well as for the development of useful implementations in biotechnology or agriculture. The research activities towards these ambitious goals are divided into three interconnected and highly collaborative work packages (WPs).

For many decades most genetic information was thought to be transacted by proteins. However, growing evidence suggests that less than 2% of the human genome encodes for proteins, whereas up to 95% of it is transcribed into RNA. These findings document the existence of an overwhelmingly large number of so far not well characterized non-coding (nc)RNAs of which many are alternatively spliced and/or processed into smaller products. These ncRNAs include miRNAs, endogenous small interfering RNAs (siRNAs) and thousands of longer transcripts (including complex patterns of interlacing and overlapping sense and antisense transcripts), most of whose functions are unknown. These RNA regulatory layers play a role in the control of chromatin architecture/epigenetic memory, transcription, RNA splicing, editing, translation and turnover. RNA regulatory networks may determine most of our complex characteristics, play a significant role in disease, and constitute an unexplored world of genetic variation both within and between species.

In this work package we explore disease-associated alterations in specific ncRNA species and aim at elucidating their biological functions and molecular mechanisms through which they contribute to disease.

Main Research Activities:

• Mechanisms and roles of RNA silencing
• RNA-mediated effects on genome and chromatin
• ncRNAs: function, disease, and therapeutic intervention

The term RNA metabolism covers a broad range of processes starting with the synthesis of RNA by transcription and ending with its degradation. Most, if not all, RNAs are processed by removal of sequences from the original transcript and, frequently, by rearrangement of the remainder. Additional sequences can be added or existing ones changed by chemical modifications. Transport processes determine the cellular localization of an RNA molecule. Additional mechanisms decide whether an RNA can fulfill its function, is kept in an inactive state, or is degraded. Each of these events contributes to the fate and regulation of the various kinds of RNAs present in a cell.

Together, these mechanisms play central roles in controlling the expression of the genetic information in cells and thereby determine developmental processes and the functionality of cells, tissues, and organs. Consequently, disturbances in any of these processes can contribute to disease. While some of these disease connections are known, well studied, and have already led to therapeutic strategies, many others remain to be discovered.
In this work package, we advance our current understanding of RNA metabolism, its regulation in health and disease, and the development of antisense-based therapeutic approaches.

Main Research Activities:

• Uncovering mechanisms of RNA metabolism
• RNA metabolism and neurodegenerative diseases
• Therapeutic modulation of RNA metabolism

Translation is one of the most fundamental cellular processes, in which the genetic code is translated into proteins. Protein synthesis is conducted by a large ribonucleoprotein complex, the ribosome. In this work package we will study the ribosome by investigating its detailed structure and function, mechanisms of its maturation and assembly, as well as the regulation of translation initiation, ribosomal quality control and degradation, and how these processes are perturbed in various diseases. In addition to the cytosolic ribosome, we will also investigate components of the mitochondrial translational machinery including the mitochondrial ribosome of the parasitic protozoa Trypanosoma brucei.

Main Research Activities:

• Eukaryotic ribosomes - their assembly, maturation and turnover
• Mitochondrial translation - a drug target against T. brucei and other trypanosomatids
• Regulation of translation and mRNA surveillance