microRNAs (miRNAs), a large class of short non- coding RNAs found in many plants and animals, often act to inhibit gene expression post-transcriptionally. 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.

In addition, we 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.
Selected publications:

The first miRNA to be identified was the product of the C elegans gene lin-4. Loss of function of lin-4 leads to overproliferation: a stem cell lineage fails to differentiate.

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.

Plain English:
My laboratory is investigating how cells decide to divide to generate all the cells of the body, to become different from each other to form different tissues such as muscle brain or blood. If cells get these decisions wrong, cancer may be the consequence. Our particular focus is a class of small regulatory genes (microRNAs) that act like molecular switches and control many aspects of development and are likely directly involved in human cancer. To better understand the biology of microRNAs we are studying a very simple animal, the roundworm Caenorhabditis elegans, as well as human cancer cells.

Selected publications:

• 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

• Clark AM, Goldstein LD,Tevlin M,Tavaré S, Shaham S, Miska EA (2010) The microRNA miR-124 controls gene expression in the sensory nervous system of Caenorhabditis elegans. Nucleic Acids Res 38(11):3780-93, Epub 2010 Feb 21

An in-vivo assay for piRNA function in the germline. PiRNAs and Piwi proteins protect the germline. We are using molecular genetics, cell biology and high-throughput sequencing to discover miRNA biogenesis and mechanisms.