microRNA; posttranscriptional regulation; RNA turnover; miRNA; C. elegans; posttranscriptional control; noncoding RNA
Miki Takashi S, Rüegger Stefan, Gaidatzis Dimos, Stadler Michael B, Großhans Helge (2014), Engineering of a conditional allele reveals multiple roles of XRN2 in Caenorhabditis elegans development and substrate specificity in microRNA turnover., in Nucleic acids research
, 42(6), 4056-67.
Hendriks Gert-Jan, Gaidatzis Dimos, Aeschimann Florian, Großhans Helge (2014), Extensive oscillatory gene expression during C. elegans larval development., in Molecular cell
, 53(3), 380-92.
Miki Takashi S, Richter Hannes, Rüegger Stefan, Großhans Helge (2014), PAXT-1 promotes XRN2 activity by stabilizing it through a conserved domain., in Molecular cell
, 53(2), 351-60.
Bossé Gabriel D, Rüegger Stefan, Ow Maria C, Vasquez-Rifo Alejandro, Rondeau Evelyne L, Ambros Victor R, Großhans Helge, Simard Martin J (2013), The Decapping Scavenger Enzyme DCS-1 Controls MicroRNA Levels in Caenorhabditis elegans., in Molecular cell
Rüegger Stefan, Grosshans Helge (2012), MicroRNA turnover: when, how, and why., in Trends Biochem Sci
, 37(10), 436-446.
Chatterjee Saibal, Fasler Monika, Büssing Ingo, Grosshans Helge (2011), Target-mediated protection of endogenous microRNAs in C. elegans., in Developmental cell
, 20(3), 388-96.
Großhans Helge, Chatterjee Saibal (2010), MicroRNases and the Regulated Degradation of Mature Animal miRNAs., in Grosshans Helge (ed.), Landes Bioscience and Springer Science and Business Media, New York, 140-155.
Grosshans Helge (ed.) (2010), Regulation of microRNAs. Adv Exp Med Biol Vol 700
, Landes Bioscience, Springer, Austin, TX, USA.
Büssing Ingo, Yang Jr-Shiuan, Lai Eric C, Grosshans Helge (2010), The nuclear export receptor XPO-1 supports primary miRNA processing in C. elegans and Drosophila., in The EMBO journal
, 29(11), 1830-9.
MicroRNAs (miRNAs) are a novel class of genes, accounting for >1% of genes in a typical animal genome. They constitute an important layer of gene regulation that affects diverse processes such as apoptosis, cell differentiation, and stem cell maintenance. Despite such critical roles, deciphering the mechanism of action of miRNAs has proven experimentally difficult, leading to multiple, partially contradictory, models of miRNA activity. Moreover, miRNAs are themselves subject to extensive, but poorly understood, regulation, providing additional layers of complexity. In order to understand how miRNAs are made and themselves regulated under physiological conditions, we will combine genetics, genomics and biochemistry in the roundworm Caenorhabditis elegans. We are particularly interested in learning about pathways of miRNA turnover, an issue of fundamental importance that has been neglected in the published body of work, although pathological consequences of miRNA over-accumulation have been widely documented. We will focus on the let-7 miRNA, an important regulator of stem cell fates. We previously showed that let-7 function is conserved between C. elegans and humans, where it functions as a tumor suppressor gene. We will therefore directly translate and test our findings in C. elegans to the regulation of let-7 in humans. C. elegans is the organism in which miRNAs were initially discovered, as were many components of the miRNA machinery, proving its utility for miRNAs studies abundantly. However, previous studies focused on genetics and cell biology approaches, limiting the degree of mechanistic insight that could be obtained. We propose here to fuse these traditional strengths of C. elegans with biochemical and genomic techniques to obtain a comprehensive understanding of miRNA function at a molecular level in a developmental context. As a proof of principle, we have recently demonstrated the utility of such a biochemical:genetic approach to determine the mode of action of endogenous miRNAs in vivo. By combining genetics and biochemistry approaches in a single system, we have the unique opportunity to address both the mode of action and the physiological relevance of the new miRNA factors. Given the importance of miRNAs in gene regulation in development and disease, such findings will be of great scientific as well as biomedical relevance.