Genome complexity: DNA 3D domain controls (Introduction)

by David Turell @, Thursday, May 18, 2017, 23:10 (275 days ago) @ David Turell

Biochemical control to isolate and separate areas of DNA found adding to evidence of very complex gene expression controls:

"After decades of research aiming to understand how DNA is organized in human cells, scientists at the Gladstone Institutes have shed new light on this mysterious field by discovering how a key protein helps control gene organization.


"The extreme compacting of DNA into chromosomes is like taking a telephone cord that stretches from San Francisco to New York, and stuffing it into a backpack," described Benoit Bruneau, PhD, a senior investigator at Gladstone and lead author of a new study. "The organization of chromosomes is not random, but rather very complex, and it is critical for normal development. When this process goes wrong, it can contribute to various diseases."

"Chromosomes are coiled into loops and then organized into many large domains called topologically associating domains, or TADs. Within each TAD, several genes and the elements that regulate them are packaged together, and they are insulated from those in neighboring TADs.

"'Imagine TADs are like adjoining rooms: like the genes in each TAD, people in each room can talk to one another, but not to people in the next room," explained Elphège Nora, PhD, postdoctoral scholar in Bruneau's laboratory and first author of the study. "In previous work, we showed that TADs package genes together and insulate them from neighboring genes. The burning question then became: what controls this TAD organization?"

"In the new study, published in the renowned scientific journal Cell, the scientists discovered that the key to organizing these TADs is a protein called CTCF.

"CTCF is a fascinating protein," said Bruneau, who is also a professor at the University of California, San Francisco. "It can be found at the boundaries of TAD domains, and was previously thought to be involved in many aspects of chromosome organization. We wanted to see what would happen to the structure of chromosomes if we removed all the CTCF from cells."


"'We noticed that, in the absence of the CTCF protein, the insulating boundaries of TAD domains had almost fully disappeared, so that genes and regulatory elements could now interact with those in adjacent TADs," added Nora. "This would be like removing the wall between adjoining rooms, so that people could now freely interact with others in the neighboring room."

"However, the absence of CTCF had little effect on how genes connect within a single TAD. This indicates that CTCF is required for insulating TADs from one another, but not for packaging genes within these domains. This represents the first conclusive study to show that the two mechanisms are separate and controlled by different proteins.


"We looked at a level of organization called compartmentalization, which separates active and inactive genes within a cell nucleus," said Nora. "This helps the cell identify which genes to use. For example, skins cells don't need eye-related genes, so these genes would be tightly packaged in a compartment and put away, because the cell will never use them. We used to think that boundaries of TAD domains were a prerequisite for the organization of these compartments."

"'To our surprise, we found that is not the case," said Bruneau. "When we deleted the CTCF protein, which caused TAD boundaries to disappear, we saw no effect on the organization of the larger compartments. This interesting finding revealed that CTCF and TAD structure are not required for compartmentalization but, rather, that an independent mechanism is responsible for this chromosome organization."

"'Our findings redefine the role of CTCF in gene regulation and provide new insights about the fundamental processes that govern genome organization" added Bruneau. "With this knowledge, we can now start reevaluating the cause of several diseases, as chromosome organization-including TADs-is often disrupted in many cancers and involved in significant developmental defects, such as congenital heart disease.'"

Comment: More and more 3-D DNA controls are found and new layers are sure to be found. These 3-D studies show the level of complexity in that DNA is more than just a linear code but has domains that must be separate and insolated and ones that must be in proximity. Not just a TAD of new complexity. Not by chance. Only a planning mind can create this. Logical.

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