New Class Of Small RNAs Discovered: Function Defined

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New Class Of Small RNAs Discovered: Function Defined

http://medicalnewscenter.com/out/out.cgi?

http://www.sciencedaily.com/releases/2009/01/090126173837.htm

Researchers at Cold Spring Harbor Laboratory (CSHL) announced today

the discovery of a new class of small RNAs. At the same time, they

reported that their discovery suggests the presence of a strikingly

novel biochemical pathway for RNA processing in which these and

possibly other small RNAs are produced.

The research, which is part of a multinational project called ENCODE,

also provided information concerning the biological function of the

new short RNA class.

The team's findings, which appeared online January 25th, ahead of

print, in the journal Nature, significantly improve our understanding

of how functional information is stored in the genome. The work at

CSHL was spearheaded by Professors Gingeras, Ph.D., a leader

of ENCODE, and Hannon, Ph.D., a world-renowned expert in

small RNAs.

" These results are a good illustration of why the ENCODE project was

established, " says Dr. Gingeras. " They show how collaborative

projects can reveal functional elements and mechanisms embodied in

the genome that have never before been described. "

Exploring vast, non-coding regions of the genome

At the conclusion of the Human Genome Project in 2003, scientists

published a final draft of the DNA sequence found within healthy

human cells ¨C an assemblage of roughly 3 billion " As " " Ts " " Cs "

and " Gs. " While justifiably proud of the feat, genome scientists knew

that the most interesting part of their task was just beginning.

Using the published 2003 sequence, they were able to specify across

the entire genome which stretches of DNA comprised genes ¨C regions

that act as blueprints for the manufacture of proteins. To the

surprise of many, those regions accounted for only about 2% of the

genome. Following that realization, most of the remaining 98% began

to look more like terra incognita than conquered territory.

To define the full set of genomic elements that perform functions in

living cells and to hunt down their location amidst the thicket of

genes and non-coding DNA, a multinational project known as ENCODE (an

acronym for Encyclopedia of DNA Elements) was initiated in 2003.

Recent research by Professor Gingeras, who has played a major role in

the project, has revealed that nearly all of the genome is converted

into various types of RNA molecules, a process once thought to be

restricted to protein-coding genes. What roles, if any, each of these

new types of RNA play within the cell is now an important topic of

research.

The world of small RNAs gets bigger

As one of the hubs of ENCODE, Gingeras's laboratory at CSHL is part

of the effort to catalogue the entire long and short RNA output of

cells. Focusing on two ENCODE- targeted human cell lines in the newly

announced results, Gingeras's group, in collaboration with Hannon's

laboratory, used powerful genome-sequencing techniques to zoom in on

small RNA molecules and select potentially new types of RNA for

further analysis.

Small RNAs are one RNA subtype among several that have been

discovered during the last decade. As a group, they are distinguished

by the fact that they do not " code " for proteins, and are physically

smaller than coding RNAs. In the small RNA group selected by the CSHL

scientists for further analysis, an abundant type is one that

Gingeras's group recently identified as arising specifically from

transcription start sites ¨C gene regions also known as promoters,

where the synthesis of protein-coding RNA molecules begins.

These promoter-associated small RNAs, or PASRs, can be contrasted

with a new species just discovered by Gingeras, Hannon and

colleagues, a type they call non-PASRs. The latter originate at sites

distant from those where PASRs are generated. Both types of small

RNAs were observed to have undergone " capping, " a chemical

modification that makes them stable and impervious to

degradation. " This quality, " Hannon observes, " lengthens their

lifespan in the cell, a clue that suggests these small RNA classes

may have significant biological duties. "

Curiously, PASRs and non-PASRs may not be initially synthesized in

their " short " form. The CSHL team proposes a model in which mature

long RNAs are cleaved followed by a capping of the newly generated

long RNA fragment. This is followed by the clipping of the end of the

capped long RNA to produce a short RNA product.

Small RNAs can act as " off " switches at " on " sites

Now that these new capped small RNA types have been discovered, the

question naturally arises: what do they do? Using a human gene called

MYC as a model, the team studied how the presence of PASRs at the

start site of a gene impacted its expression, i.e., the way it

manifested itself in a living cell. The researchers found that if the

level of expression of PASRs was increased, the expression of the MYC

gene was reduced. PASRs thus seem to modulate the production of

mature RNA transcripts.

The function of non-PASRs is unclear at the moment. This class of

RNAs " could possibly participate more globally in a bookkeeping or

quality-control mechanism by which the cell keeps track of the genes

it is expressing -- its transcriptional output, " according to

Gingeras.

This work and the future contributions of the ENCODE project have a

larger significance in understanding the genetic roots of human

disease.

" Unless we obtain much more information about non-protein coding

sequences of the genome and learn how various functional elements in

the genome impact the production of proteins, we won't fully be able

to understand the biological and clinical effects of disease-causing

mutations, " Gingeras emphasizes.

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Journal reference:

Fejes-Toth et al. Post-transcriptional processing generates a

diversity of 5¡ä-modified long and short RNAs. Nature, January 25,

2009; DOI: 10.1038/nature07759