Thursday, November 30, 2006

RNA activation of genes

The subject of RNA has come up in a number of scientific developments recently. It seems that RNA occurs in more forms and plays more roles within cells than scientists have previously supposed.

Some of the important forms that RNA can take have been known for some time. The oldest of these are messenger RNA (mRNA), which is an intermediate stage in the translation of genetic information from DNA to proteins, and transfer RNA (tRNA), which assists in the making of proteins in a ribosome. Further, ribosomes themselves are made up of some proteins and another type of RNA, ribosomal RNA (rRNA). Besides that, RNA is the genetic material of the type of viruses known as retroviruses, which include HIV.

In the 1980s, forms of RNA, called ribozymes, that act as catalysts in cellular chemistry, were discovered – and the discovery led to a Nobel Prize.

All of the forms of RNA found in cells, except for tRNA, are known collectively as non-coding RNA (ncRNA) because they do not directly encode the information in genes. Within the past 10 years a number of additional types of ncRNA have been found, including microRNA (miRNA) and small interfering RNA (siRNA).

Small interfering RNA is a big deal, big enough that the discovery has already lead to the awarding of a Nobel prize this year, though the discovery occurred less than 10 years ago:

Nobel prize for genetic discovery
Two US scientists have been awarded the Nobel Prize for medicine for their pioneering work in genetics.

The work of Dr Andrew Fire and Dr Craig Mello could lead to new treatments for a range of illnesses, including viral infections and cancer.

They discovered a phenomenon called RNA interference, which regulates the expression of genes.

The process has the potential to help researchers shut down genes which cause harm in the body.

The breakthrough has also given scientists the ability to systematically test the functions of all human genes.

The process by which siRNA can interfere with the expression of certain genes is known as RNA interference (RNAi). The process can occur by at least two mechanisms and has been thoroughly verified.

Now there is a surprizing, and controversial, claim that similar short RNA molecules can boost the expression of some genes:

How to get your genes switched on
The latest twist on the Nobel prizewinning method of RNA interference, or RNAi, could prove to be a real turn-on. Whereas standard RNAi silences a target gene, switching protein production off, the new technique boosts gene activity, providing a genetic "on" switch.

RNAi can silence genes in two ways. It can block the messenger RNA that is the intermediate between gene and protein and it can also interfere with "promoter" sequences that boost a gene's activity. It was while investigating this second phenomenon that Long-Cheng Li of the University of California, San Francisco, and his colleagues stumbled on the new method, dubbed RNA activation.

There's more detail in this article from Science (subscription rqd):

Small RNAs Reveal an Activating Side
This surprising skill--dubbed RNAa, because the RNAs activate genes--is described this week in the online edition of the Proceedings of the National Academy of Sciences. If the claim is sustained, RNAa would be a powerful biological tool and could lead to new therapies for diseases such as cancer. But some scientists say the results may reflect an indirect outcome of RNAi, rather than a new way to activate genes. "It's going to be a question of whether this holds up," says Erik Sontheimer, an RNA researcher at Northwestern University in Evanston, Illinois.

At this point, it seems that the gene activation could occur because the production of an inhibitory protein is blocked by conventional RNAi.
One key question is whether Li's RNAs are activating genes by silencing others, which would just be RNAi by another name. For example, proteins called negative transcription factors can prevent genes from being transcribed; silencing the genes for these proteins could activate genes they control.

But there is evidence that something different might be happening.
No one yet knows how small RNAs could turn genes on, especially for so long. RNAi typically silences genes for 5 to 7 days, but RNAa boosted gene activity for up to 13 days. The molecular machinery underlying RNAi appears to be involved in RNAa, raising the question of how the same enzymes can sometimes turn genes off, and sometimes on. "What makes one siRNA [small interfering RNA] a silencer, and what makes the other one an activator?" asks Sontheimer. "No clue."

Additional information:

Small dsRNAs induce transcriptional activation in human cells – original research paper (subscription rqd for full access)

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