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October 20, 2015

DNA "Backpack Buckle" Works to Regulate Gene Expression

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    The protein complex that forms DNA loops operates like the plastic slider that is used to adjust the length of backpack straps. The complex lands on DNA and takes up slack to form a loop. Researchers discovered that a specific DNA keyword called a 'motif'—a string of fewer than 20 genetic letters that causes the DNA to bind a protein called CTCF—lies at each end of nearly all loops. [A. Sanborn, S. R

    Genomic loop formation is a well-documented method that the cellular machinery uses to regulate the expression of various genes within human chromosomes. Yet, how these loops form and fold has eluded scientists for a number of years.

    Now, researchers based at Houston's Texas Medical Center have found that a protein complex that forms the gene regulatory loop works like the sliding plastic adjusters on a grade schooler's backpack—a discovery that could provide new clues about genetic diseases and allow researchers to reprogram cells by directly modifying the loops in genomes.

    "For months, we had no idea what our data really meant," explained senior author Erez Lieberman-Aiden, Ph.D., geneticist and computer scientist with joint appointments at Baylor and Rice Universities. "Then one day, we realized that we'd been carrying the solution around—literally, on our back—for decades!"

    The findings from this study were published online recently in PNAS through an article entitled “Chromatin extrusion explains key features of loop and domain formation in wild-type and engineered genomes.”

    Since many genes are activated by loops, it is impossible to understand gene activation without knowing how loops form. With that in mind, the researchers found a set of proteins that acts like the plastic slider, sometimes called a tri-glide, which adjusts a backpack strap.

    "The protein complex that forms DNA loops appears to operate like the plastic slider that is used to adjust the length of the straps: it lands on DNA and takes up the slack to form a loop," noted co-first author Adrian Sanborn, graduate student in Dr. Aiden’s laboratory.

    Because of their computer science and computational mathematics background, the investigators were able to create a tri-glide model to predict how a genome would fold. The team confirmed their predictions by making tiny modifications in a cell's genome and showing that the mutations changed the folding pattern exactly as expected. 

    "We found that changing even one letter in the genetic code was enough to modify the folding of millions of other letters," said co-first author Suhas Rao, graduate student in Dr. Aiden’s laboratory. "What was stunning was that once we understood how the loops were forming the results of these changes became extremely predictable."

    The basic idea is that the tri-glide protein complex lands on the genome and pulls the strand from each side so that a loop forms in the middle—similar to the loop one might make if they wanted to tighten a backpack strap.

    "The strand just keeps feeding through and feeding through from each direction until it hits the keyword, which acts as a brake," stated Rao.

    The researchers were excited by their findings and are continuing to generate computational models to try and explain even more genomic folding structures. In the current model, the team was amazed by the implications of their new model that loops on different chromosomes tend not to become entangled.    

    "In the old model, scientists thought that a loop formed when two bits of the genome wiggled around and then met inside the cell nucleus," Dr. Aiden remarked. "But this process would lead to interweaving loops and highly entangled chromosomes. This is a big problem if you need those chromosomes to separate again when the cell divides.

    "The tri-glide takes care of that," he continued. "Even in a big pile of backpacks, you can use your tri-glide to make a loop without any risk of entanglement."

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