Previous and current research

Important steps in the control of gene expression are executed in the cytoplasm by regulation of mRNAs via RNA-binding proteins (RBPs) and non-coding regulatory RNAs. We are elucidating these regulatory mechanisms, combining ‘reductionist’ biochemical and systems level approaches in mammalian, yeast and Drosophila model systems.

We developed the techniques of ‘mRNA interactome capture’ – to define ‘all’ RBPs associated with mRNAs in vivo (Castello et al., 2012) – and ‘RBDmap’ – to identify the RNA-binding domains of previously unknown RBPs (Castello et al., 2016). This work led to the discovery that hundreds of seemingly well characterised cellular proteins also bind RNA (enigmRBPs) (Beckmann et al., 2015). These discoveries offer an ideal starting point for exploration of ‘enigmRBPs’ and ‘REM networks’ (Hentze & Preiss, 2010), which we expect to connect cell metabolism and gene expression in previously unrecognised ways (figure 1).

Within the Molecular Medicine Partnership Unit (MMPU), we are investigating the post-transcriptional processes of nonsense-mediated decay (NMD) and 3’ end processing and their importance in genetic diseases, together with Andreas Kulozik, University of Heidelberg. Our second major interest is the biology of mammalian iron metabolism (figure 2). This work includes the definition of the functions of the IRE/IRP regulatory network and its crosstalk with the iron hormone hepcidin. Within the MMPU, together with Martina Muckenthaler, University of Heidelberg, we study the molecular basis of genetic and non-genetic diseases of human iron metabolism. Our work employs conditional knockout mouse strains for IRP1 and IRP2 and mouse models of iron metabolism diseases.

Future projects and goals

• To explore, define, and understand enigmRBPs and REM networks.
• To determine whether RNAs regulate proteins akin to protein-protein interactions
• To help elucidate the role of RNA metabolism in disease, and to develop novel diagnostic and therapeutic strategies based on this knowledge.
• To understand the molecular mechanisms and regulatory circuits underlying physiological iron homeostasis.

For research themes and projects of the teams in the MMPU, see the Molecular Medicine Partnership Unit (MMPU) and the University Hospital Heidelberg.