In our work we address the fundamental question how alternative splicing regulates cellular function and identity. Our main model systems are body temperature-controlled alternative splicing, e.g. in a circadian setting or during fever, and immune cell activation. In addition to splicing functionality, we investigate mechanisms behind signal-induced and temperature-controlled alternative splicing, with a focus on the CLK family of kinases, as their activity reacts extremely sensitive to changes in the physiologically relevant temperature range.

Our discovery that alternative splicing coupled to nonsense-mediated decay (AS-NMD) has a fundamental impact on body temperature-controlled gene expression led to our interest in using ASOs to modulate AS-NMD and gene expression in translational projects. We are for example investigating ASOs to increase the expression of the broadly neuroprotective cold-induced protein RBM3 at normothermia. See here for a newspaper article (in German) describing the potential impact of our work in developing a new therapeutic concept for age-related dementias: Tagesspiegel_Kälte_und_Gehirn. This work was also prominently featured in an article in Der Spiegel (15/2023), which highlights the broad interest in our work.

We have recently started to address alternative 3’ splice site choice, in particular NAGNAG alternative splicing and more generally tandem alternative acceptor splice site selection. In a collaborative approach we have combined cryoEM structures of spliceosomal complexes with targeted siRNA screening and structure-guided mutants of proteins in the C* complex. This led to first mechanistic insights into the regulation of alternative 3’ splice sites, which notably happens in the post-step 1 spliceosome. We are now applying this mechanistic understanding to AG-gain mutations, a large group of mutations that create alternative 3’ splice sites, thereby leading to splicing defects, which are associated with a variety of diseases.

We employ a variety of techniques ranging from bioinformatics to RNA-protein interaction assays, in vitro splicing, minigenes, cell culture and mouse models.

See here for a newspaper article describing our work connecting body temperature with viral infections (in German):   Tagesspiegel_Viren_und_Koerpertemperatur