Our laboratory is actively engaged in characterizing RNA decay pathways within mammalian nuclei. These efforts involve the identification of new pathways and components as well as their substrates. To this end, we use state-of-the-art affinity capture / mass spectrometry approaches and high throughput transcriptome-wide methodologies. However, decay of RNA is by no means just a ‘clean-up-act’ to remove worn out molecules. In addition to its essential role in the quality control of genome expression, RNA turnover is also at the core of gene expression regulation – forming intricate connections to RNA productive systems – thus, being centrally placed to determine RNA/RNP fate. Therefore, we also work towards establishing models for how regulated RNA turnover helps control key biological processes. To this end, we are mainly using mouse embryonic stem cells and their ability to differentiate and elicit various gene expression programs.

Our laboratory is studying the cytoplasmic RNA degradation pathway nonsense-mediated mRNA decay in human cells (NMD; Lykke-Andersen and Jensen, 2015). We are interested in both mechanistic aspects of NMD as well as its role in the general control of eukaryotic gene expression. In particular, we are studying the function of the endonuclease SMG6 and its interplay with other nucleases in NMD (Eberle et al., 2009; Lykke-Andersen et al., 2014). Additionally, we have recently taken an interest in the relationship between NMD and snoRNA host genes. These highly expressed genes encode mRNAs or mRNA-like transcripts from their exons and snoRNAs from one or more introns. Because maturation of intron-hosted snoRNAs generally depends on the splicing process, the spliced RNA can be considered as a by-product of snoRNA production. In many cases this ‘by-product’ acts as a normal mRNA and encodes functional protein. However, compared to general protein-coding genes, snoRNA host genes have a much more pronounced tendency to give rise to NMD-susceptible mRNAs (Lykke-Andersen et al., 2014). There are several possible explanations for this, which we are actively investigating. In combination, our studies of the mechanism and global impact of NMD may reveal novel insights about the regulation of eukaryotic gene expression.

In our lab, we use the budding yeast Saccharomyces cerevisiae to study RNA metabolism in the cell nucleus and focus on the relationships between RNA synthesis, decay and export. To identify relevant substrates of key players, we use rapid nuclear protein depletion schemes (‘anchor-away’ or ’degron’ approaches), coupled with genome-wide methodologies for measuring transcription and RNA synthesis as well as RNA fluorescense in-situ hybridization. Nuclear RNA metabolism is not only an intricate component of the gene expression machinery but also provides opportunities for regulation of transcript levels and for establishing cellular RNA homeostasis via functional coupling to transcription and cytoplasmic RNA decay. Identification of such principles is the primary target of our yeast work. Indeed, we have previously identified new paradigms for gene expression control based on polyadenylation, poly(A) binding proteins, nuclear mRNA export and RNA 3’-5’ exonucleolytic decay (Saguez et al. 2008; Schmid et al. 2012; Schmid et al. 2015; Schmid et al. 2018; Tudek et al. 2018). Consequently, our yeast work provides important insights in its own right, but also contributes important inspiration for projects in mammalian cells.