Regulation of gene expression is one of the most fascinating and most complex tasks of the cell. Expression control is achieved through multiple layers that include epigenetic, transcriptional, post-transcriptional, translational and post-translational mechanisms. The sum of these ultimately determine the expression level and activity of a given gene product, i.e. protein or non-coding RNA.
Regulation on the post-transcriptional level can be achieved by non-coding RNAs (microRNAs, long non-coding RNAs) and RNA-binding proteins (RBPs).
RBPs represent a large and heterogeneous class of posttranscriptional regulators. Through direct interactions, RBPs control the maturation, splicing, localization, stability, or translation of their target transcripts. In human diseases, e.g. in cancer, these post-transcriptional mechanisms can be disrupted due to an unbalanced expression of certain genes and their respective regulators. For example, our own studies identified the onco-fetal protein IGF2BP1 as an important pro-tumorigenic factor that can stabilize MYC transcript levels (amongst others) thereby contributing to hepatocellular carcinogenesis (Gutschner et al., Hepatology, 2014). Furthermore, RBPs can also influence the interaction of tumor cells with the tumor microenvironment by controlling the expression of cell surface receptors. In a recent study, we identified several RBPs that can regulate the expression of immune activating ligands and thus contribute to immune surveillance and escape mechanisms of cancer cells (Nachmani et al., Nature Commun., 2014).
Post-transcriptional regulation by non-coding RNAs constitutes an additional way to tune gene expression levels. Long ncRNAs, i.e. transcripts longer than 200 nt, can apply a multitude of molecular mechanisms that can include direct RNA-RNA, RNA-DNA or RNA-protein interactions. These interactions can alter the localization, translation, stability or splicing of target transcripts which can cause or contribute to human diseases, e.g. cancer (Gutschner & Diederichs, RNA Biol., 2012). Long ncRNAs can even control larger gene expression networks. For example, we previously identified the long ncRNA MALAT1 as a critical regulator of lung cancer metastasis by controlling the expression of a network of metastasis-relevant genes (Gutschner et al., Cancer Res., 2013).
These examples highlight the importance of RNA-binding proteins as well as ncRNAs as critical regulators of gene expression. The deregulated expression of these regulators can lead to altered expression levels of oncogenes and tumor-suppressors thereby contributing to tumor initiation and progression.
The research projects in our lab aim to unravel the molecular function and regulatory principles applied by non-coding RNAs and RNA-binding proteins in human cancers. To achieve this goal we will continue to develop novel genome engineering and gene targeting strategies (Gutschner et al., Genome Res., 2011; Gutschner et al., Cell Rep., 2016), which we combine with classical cell biology and biochemical approaches to dissect molecular pathways and interaction networks of these important regulators in the context of tumor biology. Ultimately, we want to identify vulnerabilities in cancers that display an unbalanced expression of ncRNAs and RBPs leveraging unbiased genetic screening tools (e.g. CRISPR/Cas9). These efforts might reveal novel therapeutic targets and treatment options.
We are always looking for motivated and talented scientists and clinicians to join our team or to collaborate with us. Please feel free to get in contact.
Jun.-Prof. Dr. Tony Gutschner (PhD)
Faculty of Medicine
Research group 'RNA-Biology and Pathogenesis'
06120 Halle (Saale)