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Architecture Reveals Genome’s Secrets

Three-dimensional genome maps are leading to a deeper understanding of how the genome’s form influences its function.

By | November 25, 2012

Human chromosome.Hans RisGenome sequencing projects have provided rich troves of information about stretches of DNA that regulate gene expression, as well as how different genetic sequences contribute to health and disease. But these studies misses a key element of the genome—its spatial organization—which has long been recognized as an important regulator of gene expression. Regulatory elements often lie thousands of base pairs away from their target genes, and recent technological advances are allowing scientists to begin examining how distant chromosome locations interact inside a nucleus.  The creation and function of 3-D genome organization, some say, is the next frontier of genetics.

Genome spatial organization is critical for gene regulation, explained Job Dekker, a molecular geneticist at the University of Massachusetts Medical School, and “everything else chromosomes do involves three dimensions,” as well. Chromosomes have to replicate, separate properly during division, and change shape during the cell cycle—all without tangling. The genome is “rebuilt entirely after cell division,” Dekker said.

The mechanisms for such delicate orchestration have remained unclear, however. About 10 years ago—just as the human genome project was completing its first draft sequence—Dekker pioneered a new technique, called chromosome conformation capture (C3) that allowed researchers to get a glimpse of how chromosomes are arranged relative to each other in the nucleus. The technique relies on the physical cross-linking of chromosomal regions that lie in close proximity to one another. The regions are then sequenced to identify which regions have been cross-linked. In 2009, using a high throughput version of this basic method, called HiC, Dekker and his collaborators discovered that the human genome appears to adopt a “fractal globule” conformation—a manner of crumpling without knotting.

In the last 3 years, Dekker and others have advanced technology even further, allowing them to paint a more refined picture of how the genome folds—and how this influences gene expression and disease states.

Conversing chromosomes

Dekker’s 2009 findings were a breakthrough in modeling genome folding, but the resolution—about 1 million base pairs—was too crude to allow scientists to really understand how genes interacted with specific regulatory elements. More detail was needed to understand how cells know which areas of the genome should be talking [to each other], and which shouldn’t,” said Dekker. After all, “you don’t want everybody talking to each other; you want [your genome] to have a decent conversation.”

Recent advances in deep sequencing are now providing researchers with a way to glean that detail. Dekker and his colleagues discovered, for example, that chromosomes can be divided into folding domains—megabase-long segments within which genes and regulatory elements associate more often with one another than with other chromosome sections. The DNA forms loops within the domains that bring a gene into close proximity with a specific regulatory element at a distant location along the chromosome. Another group, that of molecular biologist Bing Ren at the University of California, San Diego, published a similar finding in the same issue of Nature.

Between the two groups, the researchers identified these domains in mouse and human embryonic stem cells and human fibroblasts, suggesting that they are “a fundamental property of the genome,” Ren said. Additionally, both groups found that deleting boundary sections of domains threw gene regulation into disarray, causing previously silent genes to be transcribed and vice versa. These results demonstrate that “domain structure is essential to keep the gene program tightly regulated,” said Ren.

“I think the discovery of [folding] domains will be one of the most fundamental [genetics] discoveries of the last 10 years,” Dekker said. The big questions now are how these domains are formed, and what determines which elements are looped into proximity.

Chromosomes and cancer

In addition to its effect on gene regulation, chromosome folding may also play a role in cancer development. Somatic copy number alterations (SCNAs), or the deletion or amplification of genes, are a hallmark of cancer’s genomic instability. Leonid Mirny’s lab at Massachusetts Institute of Technology, who collaborated with Dekker on the 2009 discovery of “fractal globules,” found that the genome’s loops contribute to the formation of particular SCNAs. Comparing SCNA maps to the 3-D architectures of human cancer genomes, Mirny and colleagues found that genomic regions that formed the ends of the loop—and were therefore in close physical proximity—are likely to be boundaries where the intervening section is deleted or amplified, creating SCNAs.  

Translocations, or the abnormal arrangements of chromosome sections, are another hallmark of certain cancers, and also seem to be facilitated by spatial organization. Mirny and his group found that the break points for two well-known translocations—Bcr-Abl in chronic myelogenous leukemia and between Myc and immunoglobulin genes in Burkitt’s lymphoma—are frequently found near each other in normal cells, and especially in cells of the lineages prone to these tumor types. 

Tissue-specific differences in translocations may point to subtle differences in genome organization based on cell type. “Presumably in different tissue types there are specifics of the genome organization that we have yet to discover,” said Mirny. How differences in chromosome organization are achieved is another ripe area for study, said Dekker. For example, chromosome folding domains could be determined by some sort of marker in the cell, depending on type and environmental factors. “If boundaries to domains are flexible—turning on or off by cell type—suddenly genes have access to a whole new set of regulatory elements,” Dekker speculated.

In addition to better understanding cancer, chromosome folding may help predict it. As normal cells transition into tumor cells, genes can change their spatial organization in characteristic ways, said Tom Misteli, a cell biologist at the National Cancer Institute at the National Institutes of Health who is using the genome’s 3-D architecture to develop diagnostic tools. His team has shown that in breast cancer, certain genes “change position dramatically as their cells transform into cancer cells,” allowing Misteli and his colleagues to “look at an unknown tissue biopsy, localize genes, and with high accuracy determine whether its cancer or normal,” he said.

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Comments

Avatar of: Roy Niles

Roy Niles

Posts: 56

November 26, 2012

Forms only seem to influence functions.  Influence requires some form of intelligent intent or purpose.  A form's intelligence is in its function, so in the end it's the function that does the influencing of anything that forms.  Unless you have an accidental form with no function at all of course - which is likely to be impossible in a functionally formed universe.

Avatar of: John Edser

John Edser

Posts: 24

November 26, 2012

 

What concerns me is how modern genome analysis effects evolutionary theory. Darwin's pioneering work remains in a Hamilton and Dawkins inspired, gene centric dark age. Modern research is pointing one way: organism gene combinations code for phenotypes not individual genes such that each coding combination must include one non coding control gene. This strictly disallows genes their own individual fitness. Yet, Hamilton's model, which demands independent in fitness gene centricity in order to power a proposed evolution of organism fitness altruism, continues to underwrite modern evolutionary theory.  Models cannot validly replace the theory they were simplified/oversimplified from yet this was and remains the case. Hamilton et al deleted all genetic epistasis from their proposed gene centric model. Hamilton's Rule which remains the basis of Dawkins "selfish gene" centricity: rb>c provides no variable to represent genetic epistasis. I corrected this amazing omission via including the variable e allowing gene combinations to code for phenotypes: (r^e)b>c. Fact: no organism in nature is comprised of just a single locus with two alleles. Thus J.B.S Haldane who inspired Hamilton et al cannot claim to lay down his life for just 2 brothers related 0.5 or eight cousins related 0.125 but minimally, 4 brothers or 64 cousins related 0.25 and 0.015625 respectively since e=2 as a minimum. As e increases above 2 the rule becomes inoperable disallowing gene centricity. Humans have 23 chromosome pairs so a minimal human model requires e=23  putting Hamilton's c cost into the billions! Hamilton's modelling unreality has never been addressed.   John Edser   Independent Researcher   edser@ozemail.com.au   sci.bio.evolution
Avatar of: Dov Henis

Dov Henis

Posts: 14

December 14, 2012

Face Whence Whither Life

Life, genes, genomes, genetics are few of the endless things intertwined in the obvious cyclic mass-energy evolution of the universe.

Why do “scientists” persistently “research” fractional life mechanisms with obstinate refusal to view/face/comprehend the totality of the self-replicating mass format system?

http://universe-life.com/2012/12/02/earth-life-%d7%97%d7%99%d7%99-%d7%9b%d7%93%d7%95%d7%a8-%d7%94%d7%90%d7%a8%d7%a5/

Dov Henis

(comments from 22nd century)

http://universe-life.com/

Avatar of: SondraB

SondraB

Posts: 1

December 22, 2012

I found this article very compelling in that it fits the growing body of evidence that architecture and twisting, pulling our cells and molecules influence their expression.  Function is only expressed when the elements fit together in the right (or wrong) way.  Spatial organization is certainly the next frontier in biology.

How are cells arranged in the embryo to give rise to different cell and tissue types?  A study out this week on breast cancer cells showed that when they are compressed and compacted they go back to normal growth; different genes were expressed.  

Perhaps we will discover that epigenetics is a phenomenon of spatial arrangement and 3-dimensional organization.  

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