The first miRNA to be identified was the product of the C. elegans gene lin-4. Loss of function of lin-4 leads to the failure of a stem cell lineage to differentiate.
MicroRNAs (miRNAs), a large class of short non-coding RNAs found in many plants and animals, often act to post-transcriptionally inhibit gene expression. Approximately 3% of all known human genes encode miRNAs. Important functions for miRNAs in animal development and physiology are emerging. A number of miRNAs have been directly implicated in human disease. We have generated loss-of-function mutations in almost all of the 112 known miRNA genes in the nematode Caenorhabditis elegans. This collection provides the only comprehensive resource for the genetic analysis of individual miRNAs to date. Our main goal is to understand the genetic networks underlying miRNA-dependent control of development.
We are also studying other short RNA (sRNA) species, their biology and mechanism of action. For example, we recently identified the piRNAs of C. elegans. piRNAs are required for germline development and maintenance in worms, flies and mammals. Neither the biogenesis nor the mechanism of action is understood for this class of small RNAs. We are using genetic screens, biochemical and molecular biology approaches to address basic questions about sRNA biology. Of particular interest is how small RNA regulatory networks interact with the genome and the environment.
We also have developed tools for the analysis of miRNA expression in human disease and have discovered miRNAs that have potential as molecular markers for diagnosis and prognosis.
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We have discovered that let-7, LIN-28 and the poly(U) polymerase form an ultraconserved switch that regulates stem cell decisions in C. elegans.
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piRNAs and Piwi proteins are required to generate endogenous siRNAs that silence the Tc3 DNA transposon in the germline.
Lab members Javier Armisen-Garrido, Alyson Ashe, Alejandra Clark, Nic Lehrbach, Kenneth Murfitt, Alexandra Sapetschnig, Funda Sar, Eva-Maria Weick, Julie Woolford
References
Lehrbach N, Armisen J, Lightfoot H, Murfitt K, Bugaut A, Balasubramanian S, Miska EA (2009) LIN-28 and the poly(U) polymerase PUP-2 regulate let-7 microRNA processing in Caenorhabditis elegans. Nature Struct Mol Biol 16, 1016-1022
Armisen J, Gilchrist MJ, Wilczynska A, Standart N and Miska EA (2009) Abundant and dynamically expressed miRNAs, endo-siRNAs and piRNAs in the African clawed frog Xenopus tropicalis. Genome Research 19, 1766-1755
Das PP, Bagijn MP, Goldstein LD, Woolford JR, Lehrbach NJ, Sapetschnig A, Buhecha HR, Gilchrist MJ, Howe KJ, Stark R, Berezikov E, Ketting RF, Tavaré S, Miska EA (2008) Piwi and piRNAs Act Upstream of an Endogenous siRNA Pathway to suppress Tc3 Transposon Mobility in the Caenorhabditis elegans germline. Mol Cell 31, 79-90
Miska EA, Alvarez-Saavedra E, Abbott AL, Lau NC, Hellman AB, Bartel DP, Ambros VR, Horvitz HR (2007) Most Caenorhabditis elegans microRNAs are individually not essential for development or viability. PLoS Genet 3, e215
Blenkiron C, Goldstein LD, Thorne NP, Spiteri I, Chin SF, Dunning M, Barbosa-Morais NL, Teschendorff A, Green AR, Ellis IO, Tavaré S, Caldas C, Miska EA (2007) MicroRNA expression profiling of human breast cancer identifies new markers of tumour subtype. Genome Biology 8, R214