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]

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Return to the RNAi World: Rethinking Gene Expression and Evolution While investigating the genetic workings of the microscopic worm, C. elegans, Craig C. Mello and colleague Andrew Fire, PhD, of the Carnegie Institution of Washington, discovered RNAi, a natural but previously unrecognized process by which a certain form of RNA can be manipulated to silence — or interfere with — the expression of a selected gene. Mello and Fire were awarded the Nobel Prize in Physiology or Medicine in 2006. The discovery, published in the journal Nature in 1998, has had two extraordinary impacts on biological science. • One is as a research tool: RNAi is now the state-of-the-art method by which scientists can knock out the expression of specific genes in cells, to thus define the biological functions of those genes. • But just as important has been the finding that RNA interference is a normal process of genetic regulation that takes place during development. RNAi has provided not only a powerful research tool for experimentally knocking out the expression of specific genes, but has opened a completely new and totally unanticipated window on developmental gene regulation. RNAi is now showing promise in the clinic as a new class of gene-specific therapeutics.

The accompanying video is of a Google Tech Talk session conducted by Craig C. Mello on 9 April 2007. Video and abstract courtesy of Google. Time: 01:08:54.

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 work was performed by biologists at the Albert-Ludwigs-Universität Freiburg, around Dr. Wolfgang Frank and Dr. Ralf Reski. Their findings appear in the journal Cell.

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.

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.

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
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Highlights

• 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

Abstract

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.

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