Dr. Erez Lieberman Aiden holds a diagram of a 3D genome map within a cell. (320x240)
credit: Brandon Martin, Rice UniversityDr. Erez Lieberman Aiden holds a diagram of a 3D genome map within a cell.

The National Institutes of Health today announced eight mapping centers that will help lead the next four-year phase of its Encyclopedia of DNA Elements (ENCODE) Project, whose purpose is to identify all of the functional elements contained in the human genome. These eight laboratories include the Center for Genome Architecture (TC4GA) at Baylor College of Medicine, which will be responsible for mapping how the genome folds inside the nucleus of roughly 100 different types of cells. Led by Dr. Erez Lieberman Aiden, McNair Scholar and assistant professor of genetics at Baylor and Rice University, TC4GA has received $3.3 million to fund its role in the mapping effort.

The ENCODE Project was launched by the NIH’s National Human Genome Research Institute (NHGRI) in 2003, in the wake of the completion of the first drafts of the human genome’s 3 billion letter sequence. ENCODE’s goal is to decode that sequence by cataloging all the functional pieces of the human genome and to determine what each one does. These sequences include both genes and regulatory elements – the parts of the genome that control when genes turn on and off. ENCODE’s mapping centers play a crucial role in this effort. Each center is responsible for mapping one or more types of DNA sequence elements. The overall goal is to create a catalog that can serve as a resource for the entire scientific community.

“The basic idea of the ENCODE project is to create extremely detailed maps of different types of features in the genome,” Aiden said. “Then, when we put all of these maps together, the whole is much more valuable than each of the parts.”

The award to TC4GA marks the first time that ENCODE has funded a center dedicated to producing comprehensive maps of genome folding. Aiden explains that, if stretched out from end-to-end, the DNA in each cell of the human body would be over six feet long. But the DNA has to fold up to fit inside the cell's nucleus, which is less than a thousandth of an inch wide.

“This fold is not merely a way of packing a long DNA strand into a tiny space. The folding pattern is different for a heart cell that beats, a brain cell that thinks, or an immune cell that fights disease,” Aiden said.

The compact folding within the nucleus leads the genome to bend back on itself, so that two pieces that lie far apart along the DNA molecule – like a gene and its regulatory element – can come close together in the cell nucleus. Having a better understanding of where these loops occur genome-wide also will lead to a better understanding of gene regulation. 

“There are certain features that the research community feels are important to know about if we want a better understanding of how the genome works,” Aiden said. “The goal of the mapping centers is to think about these different types of features in the genome and how to detect and record them in some standardized fashion. It has become increasingly clear that genome folding plays an important role in many cellular processes. So our center will be dedicated to characterizing how the genome folds.”

Muhammad Shamim, M.D. Ph.D. student using mapping software in the Aiden lab. (320x240)
credit: Brandon Martin, Rice UniversityMuhammad Shamim, M.D. Ph.D. student, using mapping software in the Aiden lab.

The work in Aiden’s lab begins with an experiment, called Hi-C, which identifies loops and other folding features across the human genome. Aiden, together with collaborators, invented Hi-C as a graduate student and subsequently led the effort to create the first 3-D maps of the human genome in 2009. Although those very first maps were blurry, Aiden and his team at TC4GA have continued to refine the technology and improve the resolution. In 2014, a team at TC4GA led by students Suhas Rao and Miriam Huntley showed that it was possible to reliably map loops across the entire human genome – a goal that had eluded the scientific community for decades. As part of ENCODE, Aiden and his team will be performing hundreds of loop-resolution Hi-C experiments in an extraordinary range of cell types.

“Once we were able to map loops reliably, we found that we could also identify the functional sequence elements that establish the loops. Today, we are able to manipulate many of these functional elements at will, turning loops on and off and re-wiring gene regulation.”

Together with the rest of the ENCODE project, Aiden’s lab hopes to produce the most detailed picture of how the human genome works that has ever been created.

“ENCODE is an ambitious and pioneering effort in genetic research, a field where Baylor has been a world leader for decades. We hope our mapping center will continue in this outstanding tradition,” said Aiden.

View a video of Dr. Aiden explaining the ENCODE project and his work at Baylor and Rice.