|Discovery: microRNAs Can Directly Turn Off Genes|
|SciMed - Genetics & Genome|
|TS-Si News Service|
|Sunday, 10 January 2010 21:00|
Freiburg, Germany. Biologists have discovered that micro RNAs come into direct contact with genes, effectively turning off the genes in the process.
RNA molecules are the mobile messengers of genes. They carry information on the production of proteins from the DNA to the ribosomes. In addition to these messenger RNAs all living beings have micro RNAs that can hinder the messenger RNAs and protein production. [N1]
With the exception of some viruses, all living beings store their hereditary information, the sum of all their genes and non-coding information, as DNA.
In 2006 the American biologists Mello & Fire were awarded the Nobel Prize for their discovery that minute RNA molecules in the worm C. elegans can attach themselves to mRNAs and thus hinder their translation into proteins. [N2]
Active genes are transcribed into messenger RNAs (mRNAs) that function as blueprints for the production of proteins on ribosomes. Inactive genes are not transcribed into mRNAs.
The fine balance between switched-on and switched-off genes differs between organs and changes during development and under varying environmental conditions. When this balance is disturbed disfiguration and illnesses such as cancer occur.
Biologists in Freiburg together with researchers from the Max-Planck-Institute for Developmental Biology in Tuebingen have now described how microRNAs not only indirectly turn off genes by obstructing mRNAs, but can also turn off genes directly. In the process the genes are silenced chemically by adding methyl groups to the mix. In the world of Biology such changes are termed as Epigenetics.
The researchers at the Freiburg Chair Plant Biotechnology have found this novel mechanism for gene regulation in the moss Physcomitrella patens. [N3]
When the Freiburg biologists created knockout mosses, they were surprised by the effect because it contradicted all existing expectations. Now they suspect that their newly discovered mechanism for gene regulation occurs not only in moss, but also in many other life forms, including humans.
FundingThis work was supported by Landesstiftung Baden-Württemberg, the German Federal Ministry of Education and Research, the Excellence Initiative of the German Federal and State Governments, the European Community, and the German Academic Exchange Service.
Notes[N1] MicroRNAs (miRNAs) are non-coding RNAs that impact almost every aspect of biology. In recent years, they have been strongly implicated in stem cell biology, tissue and organism development, as well as human conditions ranging from mental disorders to cancer. For the most part, miRNAs control gene expression of messenger RNA (mRNA) targets. Unlike mRNAs, which are translated into proteins, miRNAs function as short, untranslated molecules that regulate specific mRNAs through base-pairing interactions. Since miRNAs bind limited stretches of consecutive bases in mRNAs, identifying which mRNAs are targets of individual miRNAs has been a bottleneck of biomedical research, as researchers have had to rely largely on computational predictions.
However, research at the University of California, San Diego have identified the binding sites of these miRNAs in one of the foremost model organisms, C. elegans, using biochemical means to capture targeted mRNA sequences in vivo. The discovery of endogenous miRNA target sites numbering in the thousands is expected to provide voluminous data on how miRNAs regulate specific targets in a developing animal. (Gene Yeo and Amy Pasquinelli; UCSD)
[N2] Classic Discoveries: Gene Silencing And The Discovery Of RNA Interference. TS-Si News Service. TS-Si (17 August 2008). Link.
[N3] Physcomitrella patens is a moss (Bryophyta), used as a model organism for studies on plant evolution, development and physiology.
ParticipantsIn addition to Wolfgang Frank and Ralf Reski, contributors included Dr. Basel Khraiwesh, M. Asif Arif, Dr. Gotelinde I. Seumel from Freiburg, and Stephan Ossowski and Prof. Detlef Weigel from the MPI Tuebingen.
CitationTranscriptional Control of Gene Expression by MicroRNAs. Basel Khraiwesh, M. Asif Arif, Gotelinde I. Seumel, Stephan Ossowski, Detlef Weigel, Ralf Reskisend, and Wolfgang Franks. Cell 2010; 140(1): 111-122. doi:10.1016/j.cell.2009.12.023
• The moss DICER-LIKE1a (PpDCL1a) protein is required for miRNA biogenesis
• The related PpDCL1b protein is required for target cleavage but not miRNA biogenesis
• In PpDCL1b mutants, genes encoding miRNA targets are silenced by DNA methylation
• This epigenetic gene silencing is initiated by high miRNA to target RNA ratios
MicroRNAs (miRNAs) control gene expression in animals and plants. Like another class of small RNAs, siRNAs, they affect gene expression posttranscriptionally. While siRNAs in addition act in transcriptional gene silencing, a role of miRNAs in transcriptional regulation has been less clear. We show here that in moss Physcomitrella patens mutants without a DICER-LIKE1b gene, maturation of miRNAs is normal but cleavage of target RNAs is abolished and levels of these transcripts are drastically reduced. These mutants accumulate miRNA:target-RNA duplexes and show hypermethylation of the genes encoding target RNAs, leading to gene silencing. This pathway occurs also in the wild-type upon hormone treatment. We propose that initiation of epigenetic silencing by DNA methylation depends on the ratio of the miRNA and its target RNA.
|Last Updated on Wednesday, 27 January 2010 13:18|