Final Report Summary - FOSRAK (Function of small RNAs across kingdoms)
The FOSRAK program addressed the importance of small RNAs in organisms across kingdoms and their major roles in regulation and modulation of gene expression. Biologically, this implies control of physiological responses, developmental checkpoints, disease associated genes, and virulence traits (in non-pathogenic and pathogenic bacteria).
The general objective was 'to advance our understanding of small RNAs and their regulatory activities beyond the current state of the art, but also to explore potential applications in the prevention or cure of diseases.' For this, a deep understanding of small RNA-mediated control of gene expression in all kingdoms of life was and is imperative. The central point is that in our current understanding - which is radically different from the perception of this topic only 10 years ago - RNAs are ubiquitous regulators rather than being merely passive transmittors of genetic information. This raises the interesting question of the relationships between, e.g. miRNAs and siRNAs (and more recent variants of this theme, like rasiRNAs, tasiRNAs, nat-siRNAs, piRNAs, or even snoRNAs) in most eukaryotes on the one hand, and small RNAs (sRNAs) in bacteria on the other. Do these functions have a common evolutionary origin? Are they different in general mechanism? Are there common denominators in structural requirements, kinetics of interaction, and in the use of helper proteins? Are there similarities in the kinds of genes regulated in different organisms (such as housekeeping genes, developmental control, stress regulation)? Are there mechanistic parallels that derive from shared physico-chemical principles, and how do different biochemical repertoires in cells of different organisms differ with specific requirements.
The work carried out by 9 partner groups from 5 countries was, thus, both geared towards an in-depth understanding of RNA-mediated regulation in a variety of chosen model organisms, and a comparative analysis that should reveal critical peculiarities / differences as well as shared principles. Based on the unique competence profiles of the participating partners, all being leaders in their particular trades, FOSRAK was in favourable position to forcefully address these questions.
The list of publications in high-ranking journals, and the frequent invitations of FOSRAK members to present talks at international meetings, write invited reviews, or be members of national or international funding and evaluation committees, indicate an excellent standing and reputation of the consortium partners in RNA biology and related subjects. The published work, and some of the completed but not yet published work, is at the forefront of this exciting field. In the three years of the FOSRAK project, great progress has been made concerning the identification of experimentally validated or strongly predicted targets for miRNAs, imprinted miRNAs, regulatory RNAs in protists and bacteria (non-pathogenic and pathogenic). The enzymology of proteins associated with, or required for, the functioning of regulatory RNAs, has been a strong focus. The role of the bacterial RNA chaperone Hfq, of the eukaryotic proteins Dicer, helicases, RNA-directed RNA polymerase (RDR or RdRp), and Argonaute proteins in RNAi / miRNA-dependent regulation, and that of ribonucleases in RNA metabolism as such and in regulation, have been fruitful areas of investigation. The pursuit of these questions has been widely documented and disseminated. The broad understanding of biological roles for some of the RNAs under study is at different stages - from solidly understood, over suggestive, to so far unresolved. The comparative aspect especially with respect to the mechanistic questions, has been and is a key element of the FOSRAK project. This question has constantly been a matter of intensive discussions whenever members of the consortium convened.
The general objective was 'to advance our understanding of small RNAs and their regulatory activities beyond the current state of the art, but also to explore potential applications in the prevention or cure of diseases.' For this, a deep understanding of small RNA-mediated control of gene expression in all kingdoms of life was and is imperative. The central point is that in our current understanding - which is radically different from the perception of this topic only 10 years ago - RNAs are ubiquitous regulators rather than being merely passive transmittors of genetic information. This raises the interesting question of the relationships between, e.g. miRNAs and siRNAs (and more recent variants of this theme, like rasiRNAs, tasiRNAs, nat-siRNAs, piRNAs, or even snoRNAs) in most eukaryotes on the one hand, and small RNAs (sRNAs) in bacteria on the other. Do these functions have a common evolutionary origin? Are they different in general mechanism? Are there common denominators in structural requirements, kinetics of interaction, and in the use of helper proteins? Are there similarities in the kinds of genes regulated in different organisms (such as housekeeping genes, developmental control, stress regulation)? Are there mechanistic parallels that derive from shared physico-chemical principles, and how do different biochemical repertoires in cells of different organisms differ with specific requirements.
The work carried out by 9 partner groups from 5 countries was, thus, both geared towards an in-depth understanding of RNA-mediated regulation in a variety of chosen model organisms, and a comparative analysis that should reveal critical peculiarities / differences as well as shared principles. Based on the unique competence profiles of the participating partners, all being leaders in their particular trades, FOSRAK was in favourable position to forcefully address these questions.
The list of publications in high-ranking journals, and the frequent invitations of FOSRAK members to present talks at international meetings, write invited reviews, or be members of national or international funding and evaluation committees, indicate an excellent standing and reputation of the consortium partners in RNA biology and related subjects. The published work, and some of the completed but not yet published work, is at the forefront of this exciting field. In the three years of the FOSRAK project, great progress has been made concerning the identification of experimentally validated or strongly predicted targets for miRNAs, imprinted miRNAs, regulatory RNAs in protists and bacteria (non-pathogenic and pathogenic). The enzymology of proteins associated with, or required for, the functioning of regulatory RNAs, has been a strong focus. The role of the bacterial RNA chaperone Hfq, of the eukaryotic proteins Dicer, helicases, RNA-directed RNA polymerase (RDR or RdRp), and Argonaute proteins in RNAi / miRNA-dependent regulation, and that of ribonucleases in RNA metabolism as such and in regulation, have been fruitful areas of investigation. The pursuit of these questions has been widely documented and disseminated. The broad understanding of biological roles for some of the RNAs under study is at different stages - from solidly understood, over suggestive, to so far unresolved. The comparative aspect especially with respect to the mechanistic questions, has been and is a key element of the FOSRAK project. This question has constantly been a matter of intensive discussions whenever members of the consortium convened.