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New view reveals how DNA fits into cell


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#1 Elus

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Posted 23 November 2009 - 04:30 AM


New view reveals how DNA fits into cell

Cells are tidy packers, cramming DNA into nuclei to create a tangle-free, dense ball with pieces that are still accessible, researchers report October 9 in Science. The findings, based on a new three-dimensional view of the whole human genome, solve a long-standing biological mystery and may lead to a deeper understanding of how genes operate.

Except during division, a human cell's two meters of DNA is jammed into an area about a hundredth of a millimeter wide. But researchers had been puzzled by how cells could pack the DNA, which is organized into 23 pairs of chromosomes inside the nucleus, so tightly without hopelessly tangling it and making it impossible to use.

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"This paper is truly outstanding because it solves a problem that's been around for a long time," comments physicist and polymer expert Gene Stanley of Boston University. "It's the question any child would ask — how does all of this DNA fit into the cell?"

One of the reasons that DNA packing remained such a mystery is that scientists lacked the tools required to assess the shape of the entire genome. Earlier studies focused on the shape of small pieces of DNA that had been chopped out, removing them from their larger context. In the new study, Erez Lieberman-Aiden of Harvard University and MIT, Nynke L. van Berkum of University of Massachusetts Medical School in Worcester and colleagues developed a trick to lock pieces of neighboring DNA to each other while they were still in the nucleus. After removing the pieces and sequencing them, the researchers could calculate how close each and every piece of DNA had been to the other pieces and could reconstruct the 3-D shape of the genome.

"Our technology allows us to ask really fundamental questions about chromosomes," says study coauthor and molecular biologist Job Dekker of the University of Massachusetts Medical School in Worcester. "It really is a radical improvement over the previous technology. It's truly genome wide and unbiased."

Applying the method to human cells, the researchers found that the genome has a highly organized structure. Small pieces of DNA fold into globs, and those globs fold into larger globs and so on. The researchers report that this "globule of globules of globules" is fractal, meaning it is organized in such a way that it has the same pattern no matter how far you zoom in. This fractal shape is "super-dense, but has no knots," says Lieberman-Aiden.

Earlier studies by Alexander Grosberg, a theoretical physicist at New York University, first predicted the fractal structure of packed DNA. "Now this paper delivers beautiful confirmation of that prediction," he says.

The new analysis also found that the genome separates into two clear compartments: One is made up of stretches of DNA known to be active and working, and the other is made up of inactive DNA, set aside for storage, Lieberman-Aiden says. "The chromosomes are kind of weaving back and forth between those compartments," he says.

Future work with more comprehensive sequencing data may even allow researchers to discern individual genes. Part of the reason scientists are so intent on understanding the shape of packed DNA is that genes can be turned on and off by far-flung DNA elements, brought together by folding. By knowing which pieces of DNA are close to each other in the pack, researchers may be able to understand more thoroughly how genes are regulated. For example, misfolding on the large scale may disrupt proper gene regulation, which could lead to cancer, Dekker says.

"Now that we know the structure, we can ask questions like, why does it look like this?" Dekker also wants to understand how a gene and a regulatory element find each other in such a dense glob. As of now, "We simply don't know," he says.

Scientists also don't yet know whether this folding pattern holds true across different cells. Dekker says that there may be "a tremendous amount of variation."

Source: http://www.sciencene...dna_globule.jpg


Edited by Elus Efelier, 23 November 2009 - 04:46 AM.


#2 AgeVivo

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Posted 13 July 2010 - 10:37 PM

very interesting, thank you. Could some global change of DNA folding be the (or a) major biological process of what we call "aging"? or do we have arguments saying that it is not?

Edited by AgeVivo, 13 July 2010 - 10:45 PM.


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#3 1101

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Posted 29 July 2010 - 03:38 PM

very interesting, thank you. Could some global change of DNA folding be the (or a) major biological process of what we call "aging"? or do we have arguments saying that it is not?


It's possible. The DNA is in that conformation for a reason and presumably it will not function as well if it gets denatured and loses this conformation (when its not supposed to anyways). Mutations in nucleotides, telomere loss, and the binding of unwanted promoters or suppressors could all theoretically change the conformation of the DNA slightly. The buildup of these changes in conformation could potentially be bad and contribute to the detrimental effects of aging. But this is just a theory. Moreover one I just made up and have no empirical reason to support. Though I don't see how DNA that isn't properly shaped could be a good thing.

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#4 ihatesnow

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Posted 02 August 2010 - 06:06 PM

http://www.the-scien.../display/57528/

#5 AgeVivo

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Posted 08 August 2010 - 11:24 AM

http://www.the-scien.../display/57528/

Thank you, we should ask him the question. If he is ok, perhaps even interview him at a sunday evening meeting

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#6 Elus

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Posted 31 October 2010 - 06:26 PM

http://www.scienceda...01029122215.htm



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.




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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."


To map both individual genes and the overall structure of the genome, Noma and his colleagues combined next generation DNA sequencing with a technique called chromosome conformation capture (3C). They then used fluorescent probes to pinpoint the exact location of specific genes through a microscope. With these data, the researchers were able to create detailed three-dimensional computer models of the yeast genome.


Using this novel approach, the researchers can view genes as they interact with each other. Noma and his colleagues can view where highly active genes are located, or see if genes that are turned on and off together also reside near each other in the three-dimensional structure of the genome. In total, the Wistar researchers also studied 465 so-called gene ontology groups -- groups of genes that share a related purpose in the cell, such as structure or metabolism.


"When the chromosomes come together, they fold into positions that bring genes from different chromosomes near each other," Noma said. "This positioning allows the processes that dictate how and when genes are read to operate efficiently on multiple genes at once."


This structure is not merely an accident of chemical attractions within and among the chromosomes -- although that is certainly a part of the larger whole -- but an arrangement guided by other molecules in the cell to create a mega-structure that dictates genetic function, Noma says. He envisions a scenario where accessory molecules, such as gene-promoting transcription factors, bind to DNA and contribute to the ultimate structure of the genome as the chromosomes fold together.


"I believe we are looking at a new way to visualize both the genome itself and the movements of all the various molecules that act on the genome," Noma said.


According to the Wistar scientists, their techniques are scalable to the human genome, even though fission yeast only has three chromosomes. In fact, the researchers found signs of "transcription factories" -- clusters of related genes that are read, or "transcribed," at discrete sites -- which have been proposed to exist in mammals.


This study was funded through a National Institutes of Health Director's New Innovator Award.


Co-authors of this study include post-doctoral researchers Hideki Tanizawa, Ph.D., Osamu Iwasaki, Ph.D., and Atsunari Tanaka, Ph.D., and Research Assistant Joseph R. Capizzi, who are all members of the Noma laboratory. They worked in collaboration with Priyankara Wickramasinghe, Ph.D., Mihee Lee, Ph.D., and Zhiyan Fu, Ph.D., of Wistar's Bioinformatics Facility.






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