Figure 1: A variety of complementary approaches will be used to derive structure-functional relationships for lncRNAs and nuclear protein complexes involved in transcription regulation.
The Marcia group uses structural biology and biophysical approaches to study the molecular interactions between long non-coding RNAs (lncRNAs) and nuclear proteins, and how their complexes regulate gene expression processes.
Previous and current research
My group studies the mechanism of lncRNA recognition within nuclear ribonucleoproteins (RNPs) and the molecular bases for their cellular functions. RNPs are involved in several physiological processes, ranging from hormone-signalling to brain function and are thus implicated in severe pathologies, including neurodegenerative and vascular diseases, developmental disorders, and cancer. Despite their crucial importance, little is currently known about the structure and mechanisms of these RNPs.
We use mainly X-ray crystallography, but also electron microscopy, small angle scattering, analytical ultracentrifugation, biochemical techniques, spectroscopy, mass-spectrometry, bioinformatics and functional assays.
Our research expertise stems from my previous work on the structure and function of various classes of macromolecules, ranging from membrane proteins to large RNA enzymes, involved in fundamental metabolic pathways such as electron transport, signalling and splicing. I previously determined the crystal structures of the bacterial sulfide quinone oxidoreductase (SQR), a membrane flavoprotein conserved also in humans, where it is involved in serious neurodegenerative diseases and lethal encephalopathies. I also determined various structures of a self-splicing group II intron, revealing the molecular mechanism behind hydrolytic splicing, including the role of monovalent ions within an unprecedented catalytic metal ion cluster. My results also shed a new light on the more complex human spliceosome.
Currently, my research aims to answer the following questions: how can many thousands different lncRNAs form tight complexes with a relatively limited set of nuclear protein complexes? Which level of selectivity characterises the formation of such complexes? How is selectivity achieved? What structural motifs are involved in recognition? How complex is the structural architecture of the intervening lncRNAs and how is it maintained? How are chromatin-binding ability and enzymatic activity of the intervening proteins regulated by lncRNAs at a molecular level? Such studies will have direct medical implications and potentially lead to the development of new therapeutic approaches to cure some of the most invasive diseases of our modern societies.
Future projects and goals
- Identify the recognition motifs that guide formation of tight complexes between lncRNAs and nuclear proteins.
- Determine structures of such ribonucleoproteins.
- Building on structural insights, understand the molecular mechanism by which lncRNAs exert their cellular functions.