Tel Aviv Israel. Scientists have unraveled how cells cn tell the difference between what is useful or not in our genetic code.

The problem is equivalent to examining a huge spool of film containing thousands of sequences of random scenes, then editing them down to a coherent — and meaningful — narrative.

The RNA "spools" that make up DNA in our genes need careful editing to ensure a quality result and avoid errors that could compromise survival of th cell, and perhaps the entire organism.

Genes are composed of meaningful sequences, called exons, separated by meaningless junk sections called introns. In order for cells to produce RNA -- the material that is required to create proteins that are vital for life -- they must precisely remove meaningless introns and bind meaningful exons together, a process called splicing.

Prof. Gil Ast, and his doctoral student Schraga Schwartz, are from the Sackler School of Medicine at Tel Aviv University. They reported their findings in Nature Structural and Molecular Biology.

Until now, how RNA was "edited" to fit together has been a mystery. The new revelations provide important information about creating proteins, and give new clues to drug developers to better understand how diseases such as cancer and genetic disorders operate at the gene level. That insight can offer significant new cellular mechanisms to create innovative drug therapies.

Rewriting DNA textbooks

In rare and common genetic disorders the DNA machinery produces non-functioning or damaging proteins in different ways. Not all genes, made from exons, produce mature RNA.If a gene skips an exon at the wrong place, non-productive, or even damaging, proteins will result. This is like building a skyscraper with faulty steel beams."We've been working on a compound, and are trying to understand how these structural marks vary between normal and cancer cells.

If we can understand how the processing of RNA is different in diseased cells, we will hopefully find something that can change it," he explains.

Prof. Ast's new observations have shown that many cellular mutations are changing the gene splicing mechanism, an area that should be targeted in drug development.

If drugs can target the mechanism that causes diseases, he hopes they will be able to halt the progression of the disease.

"These findings," says Prof. Ast, "will bring us closer to understanding diseases like cystic fibrosis and certain forms of cancer that result from our cells' failure to edit sequences properly."

"These findings," says Prof. Ast, "will bring us closer to understanding diseases like cystic fibrosis and certain forms of cancer that result from our cells' failure to edit sequences properly."

CitationChromatin organization marks exon-intron structure. Schraga Schwartz, Eran Meshorer, Gil Ast. Nature Structural & Molecular Biology 2009; 16, 990-995. doi:10.1038/nsmb.1659

Abstract

An increasing body of evidence indicates that transcription and splicing are coupled, and it is accepted that chromatin organization regulates transcription. Little is known about the cross-talk between chromatin structure and exon-intron architecture. By analysis of genome-wide nucleosome-positioning data sets from humans, flies and worms, we found that exons show increased nucleosome-occupancy levels with respect to introns, a finding that we link to differential GC content and nucleosome-disfavoring elements between exons and introns. Analysis of genome-wide chromatin immunoprecipitation data in humans and mice revealed four specific post-translational histone modifications enriched in exons. Our findings indicate that previously described enrichment of H3K36me3 modifications in exons reflects a more fundamental phenomenon, namely increased nucleosome occupancy along exons. Our results suggest an RNA polymerase II–mediated cross-talk between chromatin structure and exon-intron architecture, implying that exon selection may be modulated by chromatin structure.

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