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"Exploring the interface between cell metabolism and gene regulation: from mRNA interactomes to ""REM Networks"""

Final Report Summary - REM NETWORKS (Exploring the interface between cell metabolism and gene regulation: from mRNA interactomes to "REM Networks")

We initially developed a new technology for the discovery of RNA-binding proteins (RBP) in living mammalian cells (HeLa, HuH-7, NIH 3T3, HL-1, murine embryonic stem cells) and the yeast Saccharomyces cerevisiae (‘RNA interactome capture’). This technology was extended to plant cells and Drosophila embryos in the context of collaborations. Using this approach, hundreds of previously unrecognized RBPs were identified, shedding light on numerous aspects of RNA biology. The newly identified RBPs include dozens of enzymes of classical metabolic pathways, suggesting that these bi-/multifunctional proteins could serve to connect (post-transcriptional) gene regulation with the control of cellular metabolism, as proposed by the “REM network hypothesis”. We subjected three novel RBPs (HSD17B10, FASTKD2, sequestosome-1/p62) to functional analyses, and demonstrated biologically and medically relevant roles as RBPs for all three of these.
Furthermore, we developed a technology to systematically identify the RNA-binding domains (RBD) of RBPs in vivo (‘RBDmap’). Our studies uncovered nearly 1,200 RBDs from more than 500 RBPs. This information has implications for structural aspects of RNA-protein interactions, post-transcriptional gene regulation, and metabolism. It also serves to instruct mutagenesis experiments to determine the physiological functions of RNA-binding by classical metabolic enzymes and other RBPs. Overall, the project has yielded numerous unexpected, profound insights into RNA biology in general and RBPs specifically.