O formato do genoma é tão importante quanto seu conteúdo?

sábado, outubro 30, 2010

Is the Shape of a Genome as Important as Its Content?

ScienceDaily (Oct. 29, 2010) — If there is one thing that recent advances in genomics have revealed, it is that our genes are interrelated, "chattering" to each other across separate chromosomes and vast stretches of DNA. According to researchers at The Wistar Institute, many of these complex associations may be explained in part by the three-dimensional structure of the entire genome.

Three-dimensional structure of the fission yeast genome. (Credit: S. Pombe)

A given cell's DNA spends most of its active lifetime in a tangled clump of chromosomes, which positions groups of related genes near to each other and exposes them to the cell's gene-controlling machinery. This structure, the researchers say, is not merely the shape of the genome, but also a key to how it works.

Their study, published online as a featured article in the journal Nucleic Acids Research, is the first to combine microscopy with advanced genomic sequencing techniques, enabling researchers to literally see gene interactions. It is also the first to determine the three-dimensional structure of the fission yeast genome, S. pombe. Applying this technique to the human genome may provide both scientists and physicians a whole new framework from which to better understand genes and disease, the researchers say.

"People are familiar with the X-shapes our chromosomes form during cell division, but what they may not realize is that DNA only spends a relatively small amount of time in that conformation," said Ken-ichi Noma, Ph.D., an assistant professor in Wistar's Gene Expression and Regulation program and senior author of the study. "Chromosomes spend the majority of their time clumped together in these large, non-random structures, and I believe these shapes reflect various nuclear processes such as transcription."

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Mapping of long-range associations throughout the fission yeast genome reveals global genome organization linked to transcriptional regulation

Hideki Tanizawa, Osamu Iwasaki, Atsunari Tanaka, Joseph R. Capizzi, Priyankara Wickramasinghe, Mihee Lee, Zhiyan Fu and Ken-ichi Noma*

+Author Affiliations

The Wistar Institute, Philadelphia, Pennsylvania, USA

*To whom correspondence should be addressed. Tel: +1 215 898 3933; Fax: +1 215 573 7919; Email: noma@wistar.org

Received August 6, 2010.
Revision received September 29, 2010.
Accepted September 30, 2010.


We have comprehensively mapped long-range associations between chromosomal regions throughout the fission yeast genome using the latest genomics approach that combines next generation sequencing and chromosome conformation capture (3C). Our relatively simple approach, referred to as enrichment of ligation products (ELP), involves digestion of the 3C sample with a 4 bp cutter and self-ligation, achieving a resolution of 20 kb. It recaptures previously characterized genome organizations and also identifies new and important interactions. We have modeled the 3D structure of the entire fission yeast genome and have explored the functional relationships between the global genome organization and transcriptional regulation. We find significant associations among highly transcribed genes. Moreover, we demonstrate that genes co-regulated during the cell cycle tend to associate with one another when activated. Remarkably, functionally defined genes derived from particular gene ontology groups tend to associate in a statistically significant manner. Those significantly associating genes frequently contain the same DNA motifs at their promoter regions, suggesting that potential transcription factors binding to these motifs are involved in defining the associations among those genes. Our study suggests the presence of a global genome organization in fission yeast that is functionally similar to the recently proposed mammalian transcription factory.
© The Author(s) 2010. Published by Oxford University Press.

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