4D Nucleome (4DN)

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Program Snapshot

The goal of the 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 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.

Under different conditions, such as disease, regions of our DNA (different colored ovals) may change shape or location inside the nucleus of a cell (large circles). These movements may start or stop the production of certain proteins at the wrong time.

Resources Developed by the 4D Nucleome Program

The 4DN program has generated a variety of resources so scientists can continue to learn about the importance of nuclear organization. Program deliverables currently available through the public 4DN Portal include over 2200 datasets from hundreds of experiments, 52 software packages and 23 protocols and reagents for researchers to use.

Phase 2 of the 4D Nucleome Program

The first phase of the 4DN program was very successful, but there is still a need to deliver data and tools to the broader biomedical research community to address the role of nuclear organization in health and disease. The second stage of funding for the 4DN program is focusing on on the following initiatives:

4DN Organization and Function in Human Health and Disease
This initiative supports projects to monitor and/or manipulate the 4D nucleome in the context of human health and disease.
Real Time Chromatin Dynamics and Function
This 4DN program will focus on further developing single cell analysis technology to address how chromatin organization changes within individual cells through the the fourth dimension of time and how changes in chromatin organization affect biological processes in live cells.
4DN Centers for Data Integration, Modeling, and Visualization
Four research centers will generate comprehensive maps of genome structure, dynamics, and function using genomic and imaging data as well as newly developed analysis tools.
New Investigator Projects on 4DN Organization and Function in Human Health and Disease
4DN is supporting projects from scientists who are in the early stages of establishing an independent research career that apply new or existing tools to monitor and/or manipulate chromatin organization in the context of human health and disease
Organizational Hub and Data Coordination & Integration Center
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.

Learn more about the ongoing 4DN projects on the Funded Research page.

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In Detail

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. It is estimated that each human cell contains approximately 2 meters (6.5 feet) of DNA, squeezed inside the cell’s microscopic nucleus. We now know that DNA is not randomly arranged within the nucleus; instead, the organization of the nucleus is tightly controlled. However, the functional consequences of this organization are not well understood. What are the principles that govern the three-dimensional architecture of the nucleus, and how does this architecture contribute to gene expression regulation? How does nuclear architecture change over time (the 4th dimension) in the course of normal development? Do dysfunctional alterations in nuclear organization lead to disease, and/or could they be used to diagnose diseases?

The Common Fund’s 4D Nucleome program aims to understand the principles underlying nuclear organization in space and time, the role nuclear organization plays in gene expression and cellular function, and how changes in nuclear organization affect normal development as well as various diseases. This program is developing technologies, resources and data to enable the study of the 4D Nucleome, including novel tools to explore the dynamic nuclear architecture and its role in gene expression programs, models to examine the relationship between nuclear organization and function in both normal development and disease, and reference maps of nuclear architecture in a variety of cells and tissues.

The current phase of the 4D Nucleome program is building off of the successes of its first phase, which included six initiatives:

Nuclear Organization and Function Interdisciplinary Consortium (NOFIC):
NOFIC was composed of multidisciplinary teams that are developing and validating novel approaches and genome-wide mapping technologies that will lead to a deeper understanding of nuclear organization in time and space, and the role of this organization in regulating gene expression programs.
Nucleomics Tools:
This initiative stimulated the development and validation of chemical and biochemical technologies for measuring three dimensional interactions between specific places in the genome (genomic loci), or between genomic loci and regulators of genome organization and function, in mammalian cells.
Study of Nuclear Bodies and Compartments:
Nuclear bodies (structural and functional subunits within the nucleus) and nuclear compartments (specific subregions within the nucleus) set up distinct local environments that facilitate many important nuclear processes. This initiative supported the development of tools and strategies to study the three dimensional architecture of the nucleus in relationship to the spatial arrangement of nuclear bodies and molecular machinery regulating gene expression, the structure and function of poorly characterized nuclear structures and compartments, and the role of specialized proteins and RNAs in nuclear organization and function.
Imaging Tools:
This initiative stimulated the development of higher throughput, higher resolution and higher content imaging approaches that can measure changes in nuclear organization in live single cells.
Organizational Hub (4DN-OH) and Opportunity Pool:
The 4DN-OH developed a community website to facilitate sharing of data, reagents, standards, and protocols between 4D Nucleome investigators, and with the larger scientific community. 4DN-OH helps foster collaborations between 4D Nucleome investigators, organize yearly scientific meetings, and oversee administrative aspects of the program. 4DN-OH also administers the Opportunity Pool, a fund to support new projects and initiatives that address identified needs arising throughout the lifetime of the program.
Data Coordination and Integration Center (4DN-DCIC):
4DN-DCIC tracks, stores, and displays all data generated by 4D Nucleome investigators. It provides a Data Analysis Center to assist with integrated analyses, develops metrics and standards to be adopted by the community at large, and provides visualization tools to facilitate access and understanding of complex datasets.