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Mechanisms of microRNA biogenesis and turnover

Applicant Grosshans Helge
Number 127052
Funding scheme Project funding (Div. I-III)
Research institution Friedrich Miescher Institute for Biomedical Research
Institution of higher education Institute Friedrich Miescher - FMI
Main discipline Molecular Biology
Start/End 01.02.2010 - 31.01.2013
Approved amount 468'000.00
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All Disciplines (2)

Discipline
Molecular Biology
Biochemistry

Keywords (7)

microRNA; posttranscriptional regulation; RNA turnover; miRNA; C. elegans; posttranscriptional control; noncoding RNA

Lay Summary (English)

Lead
Lay summary
Diverse mechanisms tightly control the expression of animal genes. Recently, microRNA (miRNAs) have emerged as an important class of regulatory molecules. We will examine here how miRNAs themselves are regulated by investigating mechanisms by which they are made and degraded.Animals typically express hundreds of different miRNAs, which regulate numerous other genes, and thus affect diverse cellular and developmental processes. Conversely, miRNA deregulation contributes to various human diseases, most notably cancer. Nonetheless, the precise mechanism by which miRNAs function is poorly understood, and even less is known about how miRNAs themselves are regulated.In order to understand how miRNAs are produced and regulated under physiological conditions, we will combine genetics, genomics and biochemistry to identify and characterize novel factors involved in these processes. Our initial efforts will focus on the roundworm Caenorhabditis elegans, the organism in which miRNAs were initially identified, but we will subsequently seek to confirm and extend our findings with human cells. 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. With the widespread functions miRNAs play in various developmental pathways and in disease, understanding their regulation is of both fundamental scientific and biomedical interest. 'RNA therapeutics' are extensively investigated in the pharmaceutical and biotech industries, but are still in their infancy. By contrast, dissection of miRNA pathways will provide the basic knowledge required to pursue the modulation of miRNA activity through classical 'small molecule' drugs.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Engineering of a conditional allele reveals multiple roles of XRN2 in Caenorhabditis elegans development and substrate specificity in microRNA turnover.
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.
Extensive oscillatory gene expression during C. elegans larval development.
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.
PAXT-1 promotes XRN2 activity by stabilizing it through a conserved domain.
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.
The Decapping Scavenger Enzyme DCS-1 Controls MicroRNA Levels in Caenorhabditis elegans.
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, 281.
MicroRNA turnover: when, how, and why.
Rüegger Stefan, Grosshans Helge (2012), MicroRNA turnover: when, how, and why., in Trends Biochem Sci, 37(10), 436-446.
Target-mediated protection of endogenous microRNAs in C. elegans.
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.
MicroRNases and the Regulated Degradation of Mature Animal miRNAs.
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.
Regulation of microRNAs. Adv Exp Med Biol Vol 700
Grosshans Helge (ed.) (2010), Regulation of microRNAs. Adv Exp Med Biol Vol 700, Landes Bioscience, Springer, Austin, TX, USA.
The nuclear export receptor XPO-1 supports primary miRNA processing in C. elegans and Drosophila.
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.

Collaboration

Group / person Country
Types of collaboration
Sloan Kettering Institute United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Laval University Cancer Research Centre Canada (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Biochemical Society Focused Meeting "Biogenesis and Turnover of Small RNAs" Talk given at a conference Molecular Mechanisms and Developmental Function of MicroRNA Turnover 15.01.2013 Edinburgh, UK, Great Britain and Northern Ireland Grosshans Helge;
Conférence Jacques Monod "RNA: a key to coordination of gene expression" Talk given at a conference MicroRNAs - short but complex in function and regulation 07.11.2012 Roscoff, France, France Grosshans Helge;
EMBO/EMBL Symposium "The complex life of mRNA" Talk given at a conference The complex life of miRNA: MicroRNA Decay 07.10.2012 Heidelberg, Germany Grosshans Helge;
Fondation des Treilles "Small Silencing RNA Biology and Mechanism" Talk given at a conference Dissecting miRNA function and regulation with C. elegans 23.04.2012 Les Treilles, France Grosshans Helge;
EMBO Conference on Translational Control Talk given at a conference Active and Regulated Degradation Controls Mature MicroRNA Levels 07.09.2011 Heidelberg, Germany Grosshans Helge;
EMBO/EMBL Symposium "The noncoding Genome" Talk given at a conference Target availability legitimizes RISC residency of microRNAs in vitro and in vivo 13.10.2010 Heidelberg, Germany Grosshans Helge;


Self-organised

Title Date Place
7th Microsymposium on Small RNAs 21.05.2012 Basel, Switzerland
EMBO Conference “C. elegans: Development and Gene Expression” 17.06.2010 Heidelberg, Germany

Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Lehrerfortbildung (Sekundarstufe II) "Neue Wege der Genregulation: RNA-Interferenz" Talk 22.11.2012 Esslingen, Germany Grosshans Helge;
MipTec (Drug Discovery Conference) Talk 22.09.2010 Basel, Switzerland Grosshans Helge;


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Lehrerfortbildung (Sekundarstufe II) Neue Wege der Genregulation: RNA-Interferenz International 2012

Awards

Title Year
Boehringer Ingelheim Fonds PhD student fellowship 2010

Associated projects

Number Title Start Funding scheme
143313 Mechanisms and Developmental Functions of MicroRNA Turnover: The Exoribonuclease XRN2 01.02.2013 Project funding (Div. I-III)
114001 Computational inference of small RNA-dependent regulatory networks 01.10.2006 Project funding (Div. I-III)

Abstract

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.
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