• Until recently, scientists theorized that DNA organized itself into a structure known as an equilibrium globule, left. This type of structure is highly tangled, and stretches of DNA located near each other on a chromosome may be far apart in the 3D structure. MIT, Harvard and UMass Medical School researchers have shown that DNA is actually organized as a fractal globule, right, which resists knotting and allows DNA regions on a chromosome to remain near each other in the 3D structure.

    Images: Leonid A. Mirny and Maxim Imakaev

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A new dimension for genome studies

By revealing the 3-D structure of DNA, scientists explain how it manages to stay untangled. The findings could also help reveal how cells regulate their genes.


Scientists have long known that DNA is arranged in a double helix. But if the double helix did not fold further, each cell's genome would be two meters long — far too large to fit into the nucleus of a human cell, which is about a hundredth of a millimeter in diameter.

A new paper from scientists at MIT, the Broad Institute of Harvard and MIT, University of Massachusetts Medical School and Harvard University reveals the three-dimensional structure of the human genome and answers the thorny question of how each of our cells stows some three billion base pairs of DNA.

The work, reported in this week's issue of Science, may also explain how cells control which stretches of DNA are transcribed and which remain silent. Furthermore, the new technique could allow researchers to study how gene expression changes as cells develop or become cancerous, says Thomas Tullius, professor of chemistry at Boston University, who was not part of the research team.

"It's a whole new view of the chromosome and its place in the cell, and it's a view we've never had before," says Tullius, who studies the structure of DNA.

The new structural data reveal that the human genome is organized into two separate compartments, keeping active genes accessible while sequestering unused DNA in a denser storage compartment. Each chromosome alternates between regions of active, gene-rich DNA and inactive, gene-poor stretches.

Collaborating with physicists at MIT, genome scientists established that the genome adopts an unusual organization known in mathematics as a fractal. This architecture, called a "fractal globule," enables the cell to pack DNA incredibly tightly while avoiding the knots and tangles that might interfere with the cell's ability to read its own genome. Moreover, the DNA can easily unfold and refold during gene activation, gene repression and cell replication.

"Nature's devised a stunningly elegant solution to storing information — a super-dense, knot-free structure," says senior author Eric Lander, director of the Broad Institute, who is also professor of biology at MIT and professor of systems biology at Harvard Medical School.

Theoretical biophysicist Alexander Grosberg of New York University originally proposed a fractal globule structure for DNA in 1993. "Now it is beautifully confirmed, which is very exciting," Grosberg says.

Form follows function

Just as the 1953 discovery of the DNA double helix by James Watson and Francis Crick revealed how genetic information is stored and copied, the discovery of DNA's 3-D structure offers new insights into how cells control which sections of DNA are translated into proteins.

"It's very suggestive as to how basic cellular processes are taking place, in terms of information storage and retrieval," says co-first author of the Science paper Erez Lieberman-Aiden, a graduate student in the Harvard-MIT Division of Health Sciences and Technology (HST) and a researcher in Lander's laboratory. "It gives us a lot of ideas about how genes are turned on and off."

For example, computer simulations in the lab of MIT physicist (and HST associate professor) Leonid Mirny demonstrated that sections of a fractal globule structure can be easily opened up by chemical modification, suggesting that cells could use such modifications to control transcription of related genes located near each other.

In the past, many scientists had thought that DNA was compressed into a different architecture called an "equilibrium globule," a configuration that is problematic because it can become densely knotted and does not easily open up.

Key to deciphering the genome's structure was the development of the new Hi-C technique, which permits genome-wide analysis of the proximity of individual genes. The scientists first used formaldehyde to link together DNA strands that are nearby in the cell's nucleus. They then determined the identity of the neighboring segments by shredding the DNA into many tiny pieces, attaching the linked DNA into small loops, and performing massively parallel DNA sequencing.

Lieberman-Aiden observed that the data suggest a fractal globule. He then teamed up with Mirny and Mirny's student Maxim Imakaev to confirm his hypothesis and demonstrate conclusively that the Hi-C data matched fractal globule behavior. Computer simulations further helped to reveal biologically important features of such a DNA architecture.

In future experiments, the researchers hope to follow the development of stem cells into mature cell types such as kidney cells, says Lieberman-Aiden. "We want to understand how that process takes place, because it clearly involves some 3-D remodeling of the nucleus."

(Material from a press release issued by Harvard University and the UMass Medical School was used in this story.)


Topics: Broad Institute, Innovation and Entrepreneurship (I&E), Bioengineering and biotechnology

Comments

I found this article fascinating and so, looked up fractals on line. Of course I discovered Mandelbrot, the man who seems to be initially associated with the term fractals. I found it droll that mandelbrot itself , similar to Italian biscotti, is a twice-baked hard bread. For me, it's the repeat that's interesting as surely fractals, as in the definition below, is about repeats, or echoic patterns. The Merriam Webster dictionary definition is as follows: Main Entry: frac·tal Pronunciation: ˈfrak-təl Function: noun Etymology: French fractale, from Latin fractus broken, uneven (past participle of frangere to break) + French -ale -al (noun suffix) Date: 1975 : any of various extremely irregular curves or shapes for which any suitably chosen part is similar in shape to a given larger or smaller part when magnified or reduced to the same size
A. "New view reveals how DNA fits into cell" http://www.sciencenews.org/view/generic/id/48166/title/New_view_reveals_how_DNA_fits_into_cell A new technique allows scientists to map the 3-D structure of the entire human genome. "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. B. Maybe it looks like this since this configuration is its survival selection Maybe it looks like this since the genome is a multigenes organism as defined in the "Updated Life's Manifest May 2009" http://www.the-scientist.com/community/posts/list/140/122.page#2321 Maybe it looks like this since after all there IS something in The Lifehood Of Genes as indicated by the many pieces of the puzzle of lifehood that I've been presenting so many years. Maybe?... Dov Henis (Comments From The 22nd Century) http://profiles.yahoo.com/blog/2SF3CJJM5OU6T27OC4MFQSDYEU Implications Of E=Total[m(1 + D)] http://www.the-scientist.com/community/posts/list/180/122.page#3108
I have always wondered how fast computer cables, or more generally elongated flexible structures tend to make knots so fast. This DNA fractal organisation is perhaps suggesting how computer cables should be built so as to pack in a compact volume without making knots, and stay able to unfold easily. There is no point to patent this idea since nature has found it before.
Makes sense in either direction. Since the form (structure) was found fractal (capable of enormous amount of untangled compression), it is reasonable that the function of the genome is also fractal (See FractoGene since 2002, and The Principle of Recursive Genome Function 2008, presented in Cold Spring Harbor "Personal Genomes", 2009).
On Introns And Other Life Mysteries A. From "Introns: A mystery renewed" http://www.eurekalert.org/pub_releases/2009-12/iu-iam121009.php Intron is short for "INTRagenic regiON". Nonsense strand, noncoding DNA = DNA that does not code for part of a polypeptide chain or RNA. This includes introns and pseudo genes. In eukaryotes the majority of the DNA is noncoding. Noncoding strand refers to the so called nonsense strand, the between-genes strand, as opposed to the sense strand which is actually translated into mRNA in the expression process. The yet unsolved introns mystery includes the origin of introns configurations, how introns are gained, why they are lost, and how frequently either occurs. Almost all of the introns the IU Bloomington biologists located possessed a sequence of indeterminate origin. Only one of the 24 identified sequences bore a resemblance to a specific DNA sequences associated either with the Daphnia genome or its parasites. The other 23 introns had sequences that appear to have been improvised by the machinery responsible for DNA synthesis. "Our molecular analyses have enabled us to reject a number of hypotheses for the mechanism of intron origins, while clearly indicating an entirely unexpected pathway -- emergence as accidents arising during the repair of double-strand breaks," Lynch said. B. Re DNA methylation at CpG CpG in genetics = a site where cytosine (C) lies next to guanine (G) in the DNA sequence. The p indicates that C and G are connected by a phosphodiester bond. Methylation of DNA occurs at any CpG site. DNA methylation stably alters the gene expression pattern in cells, affecting cells to "remember" where they have been and their location-specific dictated expressions. C. From "Evolutionary Origin and Functions of Retrogene Introns" http://mbe.oxfordjournals.org/cgi/content/abstract/msp125 Exons = regions of DNA within a gene that contain the code for producing the encoded protein; these regions are not spliced out but are retained in the final mRNA molecule, The primary role and selective benefit of new introns and of UnTranslatedRegion (UTR) exons of each transcript was probably initially to span the often substantial distances to potent CpG promoters driving retrogene transcription. Later in evolution, these introns obtained additional regulatory roles in fine tuning retrogene expression levels. Our study provides novel insights regarding mechanisms underlying the origin of new introns, the evolutionary relevance of intron gain, and the origin of new gene promoters. D. From "3-D Structure Of Human Genome" http://www.sciencedaily.com/releases/2009/10/091008142957.htm Each human cell stows two meters long chain of some three billion base pairs of DNA, folded, while still maintaining access to its functionally crucial segments. The genome folds to fit into the nucleus of a human cell, which is only about a hundredth of a millimeter in diameter. The genome is organized into two separate compartments, keeping active genes separate and accessible while sequestering unused DNA in a denser storage compartment. Chromosomes snake in and out of the two compartments repeatedly as their DNA alternates between active, gene-rich and inactive, gene-poor stretches. Cells cleverly separate the most active genes into their own special neighborhood, to make it easier for proteins and other regulators to reach them. E. The introns' and other genetics mysteries will be unraveled ONLY once the lifehood of genes and genomes is recognized, and their structural and functional evolution is studied, from the origin and nature of early independent genes who lived solely on direct-sun-energy, through the evolution of genomes and cells and of their capabilities to store and exploit metabolic indirect-sun-energy, and through the life cultures of single cells communities and the evolution of some of them into multicelled organisms. It takes the adoption of the factual concepts and comprehension of the drive, origin and nature of life and of organisms to efficiently tackle and unravel the mysteries of life. Dov Henis
In health, "intense" pinching of whatever point of a leg brings about "simultaneously" microcirculatory activation of somamoto-sensorial region of parietal brain. On the contrary, in SLA Inherited Real Risk, e.g., such a activation occur after a latency time varying from two to 4 sec., showing less intense microcirculatory oscillations (See my website). In addition, in health, micorcirculatory fluctuations show high fractal dimension, while in diseased individual this dimesionality is lowered, in relation to the seriousness of underlying disorder, parallelling the impaiered dimensionality of fractal DNA.
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