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Published on Nov 16, 2008
"Hi-C: Comprehensive Mapping of Long-range interactions" Broad Institute, MIT/Harvard, 2010 (expected)
The genome is a long set of instructions that determines the development and function of a living organism. With few exceptions, every cell in the body of an organism contains a copy of its genome. These genomes are made up of long stretches of DNA, which fold up inside a cellular structure called the nucleus. If we totally unfolded the DNA living in just one of the 10 trillion cells in the human body, it would be 2 meters long. Thus the total length of DNA in the entire human body, including all its cells, is about 20 trillion meters, or five times the distance between earth and Pluto. My goal is to understand how these really long molecules folds up in order to fit inside the nuclei of our cells, which are only a few micrometers (1m/1,000,000) wide.
This dance illustrates several of the crucial steps in Hi-C, a method which can be used to identify regions of the genome that are touching each other in physical space even though they are far away if the genome is unfolded. Identifying such regions provides clues as to how a genome is folded.
The scene is set when two DNA double helixes dance into the center of the view as the genome folds into the nucleus. To accurately reproduce DNA's right-handed double helix, every dancer has their left hand placed over their right hand as they link up to each other. As the helices approach, a region of DNA from one helix makes physical contact with a region from the other.
Our goal is to identify the two regions in physical contact. We can identify these connected regions using the following experimental technique. First a 'restriction enzyme' is used to cut the genome into many tiny fragments. The result is that fragments which are not in physical contact float away from each other, but those which are stuck together don't separate. You can see how Anna, the restriction-enzyme-dancer, cuts the helices apart.
Next, Lisa the ligase-dancer shows how DNA ligase is used to transform the two fragments of DNA that are stuck together into a new DNA loop. This DNA loop dances off the screen where it can be sequenced and analyzed, yielding valuable information about which regions of DNA are in contact.
Performed at the Hertz Foundation Fellowship retreat Harvard Forest museum, 15 November 2008