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===Global analysis of post-transcriptional gene regulation===
===Control of Post-transcriptional gene regulation by RNA-binding proteins===


Post-transcriptional control of gene expression involves RNA processing, transport, turnover and mRNA translation. Regulation of these steps has substantial effects on the expression and function of genes in diverse processes such cytokinesis, embryonic development, neurogenesis and cancer progression. RNA-binding proteins (RBPs) have been implicated in diverse aspects of post-transcriptional gene expression. Hundreds of RBPs are encoded in eukaryotic genomes, and whereas many classical studies explored the cellular role of RBPs with specific mRNA substrates, the recent development of genome-wide analysis tools enables systematic identification of mRNA substrates of RBPs, and the study of post-transcriptional gene regulation on a global scale. Importantly, these studies revealed that many RBPs bind to and regulate subsets of mRNAs, which encode proteins that are localized to the same subcellular compartment, act in the same pathway or are components of macromolecular complexes. Moreover, these sets of mRNAs often contain characteristic sequence elements in the 3'-untranslated regions, which are potential binding sites for regulatory RBPs (Gerber et al. 2004). These findings strongly indicate the presence of extensive post-transcriptional regulatory systems in eukaryotic cells, which may be comparable in its extent and richness to that of transcriptional regulatory networks.
Gene expression must be tightly controlled to ensure coordinated synthesis of the cells’ macromolecular components. Besides transcriptional control, it has become evident that also the later post-transcriptional steps – namely the processing, transport, turnover and translation of mRNAs – are pivotal for the diversification and spatiotemporal control of gene expression. Hundreds of RNA-binding proteins and non-coding RNAs mediate post-transcriptional control with widespread implications in cell physiology and disease. Nevertheless, the targets and functions for most RNA-binding proteins and non-coding RNAs are still not known.


We are interested in exploring this RBP-mediated post-transcriptional program. We use genome-wide analysis tools like DNA microarrays to elucidate basic principles (e.g. systematically map RNA-protein interactions), and we apply ‘classical' biochemical, genetic and cell-biological methods to further investigate specific functional aspects of the RNA-protein network. We use yeast as model system to establish techniques for the global analysis of RNA regulation, and to investigate basic principles. In addition, we study the post-transcriptional program in mammalian cells and investigate how it may be perturbed in certain disease states (e.g. tumorigenic cells).<br/><br/>
We have been combining genome-wide analysis with classical biochemical and genetic tools to identify the RNA targets of RNA-binding proteins and to investigate post-transcriptional gene regulation on a global scale. Importantly, these studies revealed that RNA-binding proteins bind to and coordinate groups of mRNAs that code for proteins, which are localized to the same subcellular compartment, act in the same pathway or are components of macromolecular complexes, forming so-called RNA regulons. Moreover, these set of RNAs often bear conserved sequence/ structural elements that likely represent binding sites for RNA-binding proteins. These findings suggested the presence of a highly-organized and elaborate post-transcriptional regulatory system that may affect virtually every mRNA in a cell.
 
We are further exploring the post-transcriptional regulatory landscape. On the one hand, we study specific RNA-binding proteins that coordinate the localization, decay or translation of mRNAs in the cytoplasm. On the other hand, we characterize the translatome – which refers to all mRNAs that are associated with ribosomes for protein synthesis (Halbeisen et al. 2009) – and we monitor its reaction upon stress or drug treatment of cells and in pathological conditions. We primarily use budding yeast as model to establish new techniques and to elucidate principles of post-transcriptional control, and we work with mammalian cells to unravel implications in disease. <br/><br/>


'''Reviews:'''<br/>
'''Reviews:'''<br/>
*King, H.A., Gerber, A.P. (2014) Translatome profiling: methods for genome-scale analysis of mRNA translation. Brief. Funct. Genomics, doi:10.1093/bfgp/elu045
*Imig, J, Kanitz, A, Gerber, AP (2012) RNA regulons and the RNA-protein interaction network. BioMol. Concepts, 3, 403-417.
*Imig, J, Kanitz, A, Gerber, AP (2012) RNA regulons and the RNA-protein interaction network. BioMol. Concepts, 3, 403-417.
*Kanitz, A, Gerber, AP (2010) Circuitry of mRNA regulation. Wiley Interdisciplinary Reviews: Systems Biology and Medicine 2, 245-251.
*Kanitz, A, Gerber, AP (2010) Circuitry of mRNA regulation. Wiley Interdisciplinary Reviews: Systems Biology and Medicine 2, 245-251.

Revision as of 05:22, 27 November 2014


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Control of Post-transcriptional gene regulation by RNA-binding proteins

Gene expression must be tightly controlled to ensure coordinated synthesis of the cells’ macromolecular components. Besides transcriptional control, it has become evident that also the later post-transcriptional steps – namely the processing, transport, turnover and translation of mRNAs – are pivotal for the diversification and spatiotemporal control of gene expression. Hundreds of RNA-binding proteins and non-coding RNAs mediate post-transcriptional control with widespread implications in cell physiology and disease. Nevertheless, the targets and functions for most RNA-binding proteins and non-coding RNAs are still not known.

We have been combining genome-wide analysis with classical biochemical and genetic tools to identify the RNA targets of RNA-binding proteins and to investigate post-transcriptional gene regulation on a global scale. Importantly, these studies revealed that RNA-binding proteins bind to and coordinate groups of mRNAs that code for proteins, which are localized to the same subcellular compartment, act in the same pathway or are components of macromolecular complexes, forming so-called RNA regulons. Moreover, these set of RNAs often bear conserved sequence/ structural elements that likely represent binding sites for RNA-binding proteins. These findings suggested the presence of a highly-organized and elaborate post-transcriptional regulatory system that may affect virtually every mRNA in a cell.

We are further exploring the post-transcriptional regulatory landscape. On the one hand, we study specific RNA-binding proteins that coordinate the localization, decay or translation of mRNAs in the cytoplasm. On the other hand, we characterize the translatome – which refers to all mRNAs that are associated with ribosomes for protein synthesis (Halbeisen et al. 2009) – and we monitor its reaction upon stress or drug treatment of cells and in pathological conditions. We primarily use budding yeast as model to establish new techniques and to elucidate principles of post-transcriptional control, and we work with mammalian cells to unravel implications in disease.

Reviews:

  • King, H.A., Gerber, A.P. (2014) Translatome profiling: methods for genome-scale analysis of mRNA translation. Brief. Funct. Genomics, doi:10.1093/bfgp/elu045
  • Imig, J, Kanitz, A, Gerber, AP (2012) RNA regulons and the RNA-protein interaction network. BioMol. Concepts, 3, 403-417.
  • Kanitz, A, Gerber, AP (2010) Circuitry of mRNA regulation. Wiley Interdisciplinary Reviews: Systems Biology and Medicine 2, 245-251.
  • Halbeisen, R, Galgano A, Scherrer T, Gerber AP (2008) Post-transcriptional gene regulation: From genome-wide studies to principles. Cellular and Molecular Life Sciences 65(5):798-813.


Different proteins assemble on a given message to form an mRNP, the composition of which changes dynamically, depending on the cellular context. The combinatorial control of associated regulatory, scaffolding and accessory proteins ultimately determines the mRNA fate ("mRNP code").