Researchers win $12-million to study the human genome in 4-D

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Researchers win $12-million to study the human genome in 4-D

Project seeks to understand how a 6.5 feet of DNA folds to fit inside a cell
Michael McCarthy

In order to fit within the nucleus of a cell, the human genome must bend, fold and coil into an unimaginably compact shape – and still function. This is no mean feat: The human genome is about 6.5 feet long, and the average cell nucleus is only 6 to10 micrometers (one-millionth of a meter) in diameter. 

How this happens and the genome's three-dimensional shape within the nucleus are unknown. Nor is it known how the shape changes over time – the fourth dimension – as a cell develops, grows and goes about its specialized functions.

“There’s a tendency to talk about the genome as a linear sequence and to forget about the fact that it’s folded,” said Dr. Jay Shendure, University of Washington associate professor of genome sciences and investigator with the Howard Hughes Medical Institute.  

William Noble, left, and Jay Shendure will co-direct the UW Center for Nuclear Organization and Function.
pictures of William Noble and Jay Shendure

“To understand how the different parts of the genome talk to each other to control gene expression, we need to understand how the different elements are arranged in relation to each other in three-dimensional space.”

To puzzle out this information and its effect on cell function in health and disease, UW researchers will join peers at five other academic institutions to create the Nuclear Organization and Function Interdisciplinary Consortium. 

Underwriting the consortium is the National Institutes of Health’s 4D Nucleome program. The UW was awarded $12 million over five years to conduct research in its new Center for Nuclear Organization and Function. Shendure and William Stafford Noble, a professor of genome sciences and computer science, will co-lead.

UW researchers will first develop tools to work out the three- and four-dimensional architecture of the nucleome and to create computer models that predict changes in the architecture as cells grow, divide and differentiate into different types. 

The results of this work will then be tested in mouse and human cell lines and, if confirmed, be used to understand how changes in nuclear architecture affect development of normal and abnormal heart muscle. 

All tools and data developed by the project will be shared with researchers in and outside of the 4D Nucleome network of researchers and with the public.

Other investigators who will be working on the project include: Cole Trapnell, assistant professor of  genome sciences; Christine Disteche, professor of pathology; Zhijun Duan, research assistant professor of medicine (hematology); and Dr. Charles Murry, professor of pathology and interim director of the UW Institute of Institute for Stem Cell and Regenerative Medicine.