Long non-coding RNAs act like enhancers of gene regulation

Scientists describe novel mode for regulation of gene activity

The regulation of gene activity belongs to the most challenging questions of modern biology. So far, scientists know only a few mechanisms to switch single genes on or off. Now, an international team of scientists from the US, Germany, and Spain has described a new mode to regulate gene activity. In the current issue of the scientific journal “Nature” Ulf Andersson Ørom, head of a research group at the Max Planck Institute for Molecular Genetics in Berlin, in collaboration with researchers from the Wistar Institute in Philadelphia, the Children’s Hospital of Pennsylvania, the University of Colorado, and the Center for Genomic Regulation in Barcelona, Spain, show that long non-coding RNAs bind to mediator, a multiprotein complex, thus enabling it to bind to the DNA and initiate the transcription of several genes.

Quite surprisingly, the first sequencing of a human genome revealed that human beings only possess around 20,000 genes – about as much as a nematode and much less than a water flea. However, the genes involved directly in protein production, are only a small part of the genome. Today, we know that the bigger part, formerly thought of as junk DNA, does also contain vital information, especially for the regulation of gene activity.

But how is a gene actually switched on or off? What determines the activity of genes at the right time and in the correct tissue? Scientists assume that quite a substantial part of non-coding DNA participates in gene regulation. Already in 1981, short non-coding DNA regions with characteristic base sequence have been described, which are able to increase the transcription rate of gene. These so-called enhancers bind protein complexes and are thus initiating gene transcription. Crucial for their function is the spatial arrangement of the enhancer in relation to the gene. Some of them are known to lie up to one million base pairs up- or downstream a respective gene, but due to the three-dimensional structure of the DNA, they are still located near the origin of the gene.

In 2010, Ørom and his co-workers have been able to identify a group of non-coding DNA regions, operating only after their transcription to long non-coding RNA molecules. These molecules, termed non-coding RNA-activating (ncRNA-a) stay inside the nucleus after transcription and modulate gene activity in an enhancer-like way. “Now, we have been able to report on the precise mode by which such enhancer-like RNAs function”, Ørom explains his results. “Contrary to normal enhancer molecules that are part of the DNA, enhancer-like ncRNA-as are able to move around in the nucleus. Thus, they are also capable of modulating genes whose positions are far away on the DNA strand.” The new results show ncRNA-as to associate to a large protein complex, called Mediator, acting in mediating the function of several enhancers in human. The results have an immediate impact on the general understanding of enhancer function and deepen our understanding on how gene expression is regulated.

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