The goal of the National Insitute of Health’s (NIH) Common Fund’s 4D Nucleome (4DN) program is to study the three-dimensional organization of the nucleus in space and time (the 4th dimension). The nucleus of a cell contains DNA, the genetic “blueprint” that encodes all of the genes a living organism uses to produce proteins needed to carry out life-sustaining cellular functions. Scientists know that how the information in the nucleus is organized, stored, and unpackaged are all important to basic human health and we are only starting to learn how changes in this organization can lead to the development of different diseases, such as cancer or our response to infectious agents like viruses.
In 2017, the 4DN program has made awards for its second stage. A total of thirty awards have been made for six initiatives. The 4DN program will continue to support research on the three-dimensional organization of the nucleus and how it shifts over time (the fourth dimension). Stage 1 of 4DN successfully developed important technologies and datasets that will be leveraged in Stage 2.
Six projects from early stage investigators are supported by the New Investigator Projects on 4DN Organization and Function in Human Health and Disease. The 4DN program will focus on further developing single cell analysis technology to address the fourth dimension of time. This will be carried out through the eight projects of the Real-Time Chromatin Dynamics and Function initiative. As part of the 4DN Centers for Data Integration, Modeling and Visualization, four research centers will generate comprehensive maps of genome structure, dynamics and function. The 4DN Organizational Hub will continue to administer and coordinate the consortium, and the 4DN Data Coordination & Integration Center will continue to be responsible for data collection, storage, curation, and dissemination.
The nucleus is the control center of the cell, packed with 6 linear feet of DNA in a space narrower than the width of a human hair. Since it began, research supported by the 4D Nucleome (4DN) program has improved our understanding of how DNA is packaged and organized in the crowded space of the nucleus. Advancements by the program have prompted scientists to develop new methods to get an even clearer picture of how the DNA is organized. These methods are beginning to give us a good grasp on how large areas of DNA are packaged into different compartments, where portions of DNA that would be far apart in a piece of DNA stretched out long, are actually located close to each other in the nucleus, similar to if you scrunched up a long piece of string and placed it in a ball. Understanding how DNA is organized in three dimensions has informed scientists how that organization can alter which genes are turned on or off, an important factor in many diseases such as cancer. We can now see how large portions of DNA are situated, but can more information be gathered by looking at how smaller regions of DNA in the nucleus are organized?
A team of researchers led by Drs. Xavier Darzacq and Job Dekker, whose research is supported by the 4DN program, developed a new method, called Micro-C, to provide a better image of how smaller regions of DNA are organized in three dimensional space. Looking at the DNA in a mouse model system, the team demonstrated that smaller-than-previously-thought regions of DNA can control gene activity and that the closeness of these small regions is important in recruiting proteins to control how genes are turned on or off. A companion study mirrored these studies demonstrating that Micro-C is suitable for human cells as well. The development of this new method will help strengthen our understanding of how genes are spatially controlled in the crowded nucleus and may provide opportunities for developing future treatments as we learn more about gene activity regulation in healthy and diseased cells.
