Helping unravel the function of microRNAS

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Helping unravel the function of microRNAS

01 Jul 2005 Medical News Today

MicroRNAs are a recently discovered large class of small, non-coding

genes. Each animal genome contains hundreds of these genes, which

have been shown to regulate the expression of protein coding genes by

binding to partially complementary sites in messenger RNAs. However,

little is known about the biological function of these tiny genes,

which are encoded in a string of 21 to 24 DNA bases.

In a series of four high-profile papers in Nature, Nature Genetics,

Developmental Biology, and PloS Computational Biology published over

the past 15 months, researchers at New York University's Center for

Comparative Functional Genomics have shed light on the function and

evolution of microRNA across a wide set of genomes. Their newest

findings appear in the inaugural issue of Public Library of Science's

journal, PloS Computational Biology.

This study, headed by NYU Assistant Biology Professor Nikolaus

Rajewsky, included researchers Dominic Grün, Yi-Lu Wang, and

Langenberger, and Research Assistant Professor Gunsalus, all

at NYU's Center for Comparative Functional Genomics. By comparing

seven recently sequenced fly species, they found that thousands of

genes in the genome of a laboratory model organism--the fruit fly--

are likely to be regulated by microRNAs.

The researchers could also predict a specific biological function for

70 percent of all of these microRNAs. The predictions in the study

are publicly available at pictar.bio.nyu.edu/. The paper also shows

that microRNAs that are conserved between flies and mammals are

likely to target the same proportion of genes in each species,

although the number of conserved regulatory relationships is

relatively small.

These findings hint at a significantly larger role for microRNAs

during evolution. Evolutionary changes in which genes are targeted by

certain microRNAs could thus help to explain differences between

species, implicating that microRNAs could be part of genes that drive

organismal diversity. In particular, one microRNA was shown to have

many more targets in flies than in mammals, and this microRNA was

predicted to contribute to the regulation of fly oogenesis, a process

that is highly different between flies and mammals.

The paper may be obtained at compbiol.plosjournals.org

In carrying out the study, the Rajewsky group developed " PicTar, " a

new algorithm for the identification of microRNA target sites in the

genome (published in Nature Genetics, spring 2005). The PicTar

algorithm was based on a paper by Rajewsky, who also holds an

affiliated appointment at NYU's Courant Institute of Mathematical

Sciences, and his collaborator Socci published in

Developmental Biology in 2004, where they discovered key components

of microRNA--target site recognition. When applying PicTar to seven

vertebrate genomes, their Nature Genetics study found that each

microRNA regulates, on average, 200 different human transcripts and

that multiple microRNAs can coordinate their activities to regulate a

specific target genes. Altogether, they showed that 20 to 30 percent

of all vertebrate genes are likely to be regulated by microRNAS. The

paper contains detailed genome-wide target predictions for all human

microRNAs as well as tissue-specific predictions. Several predictions

were validated experimentally by Rajewsky's collaborators at

Rockefeller University. The findings demonstrate an unforeseen,

staggering complexity of gene regulation executed by microRNAs on a

genome-wide level.

Finally, collaborating with researchers at Rockefeller University,

Lund University (Sweden), and Oxford University, Rajewsky recently

helped to unravel the function of a microRNA gene that was shown to

regulate the secretion of insulin in the pancreas. The findings,

which for the first time defined a physiological function for a

mammalian microRNA gene, were published last fall in Nature. In the

study, predicted gene targets for miR-375 were verified

experimentally, thereby making an important contribution for

understanding miR-375 function in regulating insulin secretion, and

potentially opening the door for new ways to treat diabetes.

EDITOR'S NOTE

New York University's Center for Comparative Functional Genomics

seeks to define how regulatory networks operate and how they have

evolved to generate diversity across species. For this work, it uses

approaches that span systems biology, comparative functional genomics

and bioinformatic analysis. The research involves the combined skills

of genomicists, bioinformaticians, systematists, and evolutionary

biologists. The genomic and bioinformatic faculty in our center are

engaged in collaborative projects with scientists at NYU's Courant

Institute of Mathematical Sciences, the American Museum of Natural

History (AMNH), the New York Botanical Garden (NYBG), and Cold Spring

Harbor Laboratories (CSHL), as well as collaborators at Harvard and

Rockefeller University.

PLoS Computational Biology is an open-access, peer-reviewed journal

published monthly by the Public Library of Science (PLoS) in

association with the International Society for Computational Biology

(ISCB).

New York University

http://www.nyu.edu