Gene expression in mammalian cells is tightly controlled at many levels - from RNA transcription, processing and degradation, to mRNA translation and protein degradation. Although studies of individual genes have shown the importance of regulating each of these processes for correct protein expression, the fields of molecular, cell and developmental biology have mostly focused on transcriptional control as the primary mode of gene regulation. Yet several studies comparing RNA and protein abundances have indicated a considerable discrepancy between RNA and protein levels. Moreover, many genes, encoding for proteins that regulate mRNA translation are recurrently mutated in diseases, such as cancer and neurological disorders, suggesting that mRNA translation are important in both health and human disease. The overarching research goal of the lab is to understand the principles and mechanisms by which translational regulation controls the dynamics of gene expression and therefore affects processes like differentiation, stress response and pathogenesis.
RNA Binding Proteins
The mammalian genome encodes over 1,500 RNA Binding Proteins (RBPs), a number rivalling and even exceeding that of transcriptional regulators, and most of these RBPs are highly conserved, suggesting that gene expression is also tightly regulated at the post-transcriptional level. Furthermore, several RBPs are recurrently mutated in diseases such as cancer, immunoregulatory disorders, spinal muscular dystrophy and other neurological disorders, demonstrating the importance of post-transcriptional gene regulation—especially mRNA translation—in both health and human disease. Despite mounting evidence for the importance of RBPs in mRNA translation regulation, knowledge about their function has remained limited to a few isolated examples, and for many of the predicted 1,500 RBPs no physiological function has yet been assigned. Therefore, a systematic and comprehensive way to study the regulation of mRNA translation by RBPs, a fundamental step in gene expression regulation, is desperately needed.
Translational Regulation in the 5’ UTR
We recently uncovered a novel and unconventional mode of gene regulation in yeast. This novel mechanism involves temporally regulated switching between production of a canonical, translatable transcript and a 5’ extended isoform, termed “long undecoded transcript isoform (LUTIs)”, that is not efficiently translated into protein. By this pervasive mechanism a single transcription factor can coordinately activate and repress protein synthesis for distinct sets of genes. Currently we are testing if this novel regulatory mechanism is also conserved in higher eukaryotes, specifically during ES cell differentiation.
We are focusing on several aspects of technology development in order to acquire improved and/or novel large-scale data sets that would help us to better answer the biological questions arising in the lab. We are developing novel proteomics methods to quantify total protein levels and changes in posttranslational modifications at higher quantitative accuracy, sample throughput and the need for less input material. Moreover, molecules do not work in isolation but through interactions, which change in time and space. For example, RBPs often co-bind with other RBPs to the same mRNA and by interaction with the translational machinery either activate or repress translation. However, there are no universal and easily implementable tools available to measure dynamics of protein-protein interaction networks. We are developing such a novel scalable approach to map protein-protein interactions and the dynamics of these interactions that can be applied to hundreds to thousands of proteins and experimental conditions simultaneously.