New Way Nature Turns Genes On And Off

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New Way Nature Turns Genes On And Off, Jefferson University

http://www.medicalnewstoday.com/medicalnews.php?newsid=59805

Peering deep within the cells of fruit flies, developmental

biologists at the Kimmel Cancer Center at Jefferson

University in Philadelphia may have discovered a new way that genes

are turned on and off during development. If they're right, and the

same processes are at work in higher organisms, including mammals,

the findings could eventually have implications for improving the

understanding of a range of diseases, including childhood cancer.

Reporting in the journal Cell, Mazo, Ph.D., professor of

biochemistry and molecular biology at Jefferson Medical College,

Svetlana Petruk, Ph.D., and their co-authors focused on pieces of

genetic material called non-coding (nc)RNAs. About two-thirds of the

human genome is converted into such RNAs (the better known messenger

RNAs are translated into proteins), though the function of the

majority is unknown. The researchers detailed a possible mechanism

by which ncRNAs briefly control the functioning of homeotic, or HOX,

genes, which guide the master developmental plan of the organism.

" We think that this new mechanism operates early in embryogenesis, "

says Dr. Mazo.

According to Dr. Mazo, the researchers found that one of the likely

mechanisms behind ncRNAs' ability to regulate essential coding genes

is through a " transcription interference " mechanism. " Such

mechanisms are known in bacteria and yeast, but not much is known in

higher organisms, " he explains.

In the fruit fly, HOX gene activity is maintained by genes and

proteins in the Trithorax group (TrxG). These proteins are thought

to act through so-called maintenance elements, one of which, in a

nearby region, bxd, is located between two HOX genes, Ubx and abd-A.

Dr. Mazo explains that several " long " ncRNAs are transcribed through

bxd maintenance elements. They were thought to be expressed in the

same cells as Ubx, and to regulate HOX gene coding sequence

expression. But the researchers found something different: ncRNAs

instead can repress Ubx activity by blocking its activity in certain

types of cells in the developing embryo.

" Importantly, non-coding RNAs are very tightly developmentally

regulated, as we show in case of bxd RNAs, " Dr. Mazo notes. " These

create an enormous potential to regulate the neighboring coding

genes in a time- and tissue-specific manner. This is a new type of

transcriptional regulation mechanism for higher eukaryotes, and it

is very likely that it is conserved in mammals. "

Understanding the details of the TrxG system could someday have

implications for ALL, a dangerous type of childhood leukemia. The

disease stems from gene rearrangements in utero. MLL, the gene that

is affected in humans, corresponds to Trithorax in fruit flies. " ALL

is thought to be a disease of misregulated HOX genes, " says Dr. Mazo.

HOX gene groups have long been known to be " transcriptional

regulators " that control the multitude of genes involved in

embryonic development, Dr. Mazo says. He and his group would like to

ultimately better understand the early stages of such development.