New research is underway to better understand the nucleus, the control center of our cells.

Teams from two divisions of the Allen Institute, the Allen Institute for Cell Science and the Allen Institute for Brain Science, are participating in newly launched projects to address unanswered questions in nuclear biology. Both projects are part of 4DN Centers for Data Integration, Modeling and Visualization of the National Institutes of Health Common Fund 4D Nucleome program.

The nucleus houses all of our chromosomes — our genome — and our DNA’s many associated proteins that regulate its organization and gene activity. If laid end-to-end, the entire string of a single human cell’s genome would stretch about 6.5 feet long. But each of our cells has to fit all that DNA into the nucleus, a microscopic structure less than a fifth the width of a human hair.

It’s not just a packing problem — the nucleus’s organization needs to grant proteins access to DNA to read out its genes, to replicate the DNA every time the cell divides, to switch off genes that need to remain silenced. This organization also changes in different cell states, between cell types, and in disease. There’s a whole city’s worth of architecture inside each human nucleus, and scientists still understand very little about its rules and structure.

The 4D Nucleome Program was launched in 2015 to tackle these problems through large research collaborations. The newly announced grants are part of the second phase of the program.

Both Allen Institute projects will focus on how mammalian genomes are organized in 3D in the nucleus, and how that organization changes over time or between cell states or types, one with a focus on human stem cells and the other focused on human and mouse brain cell types.

The Allen Institute for Cell Science project is part of a collaborative center titled “Multiscale Analyses of 4D Nucleome Structure and Function by Comprehensive Multimodal Data Integration,” which is headquartered at Carnegie Mellon University and led by Jian Ma, Ph.D., associate professor of computational biology. The CMU center aims to develop a better understanding of the three-dimensional structure of cell nuclei and how changes in that structure affect cell functions in health and disease. Susanne Rafelski, Ph.D., Deputy Director and Director of Assay Development at the Allen Institute for Cell Science is leading a team that will construct 3D models of the nucleus and some of its major internal compartments based on image data from live human stem cells. These models will then be merged into 3D models of the human genome that are being constructed by their collaborators in the CMU-led center

This merging of models will help the researchers understand important details about how the genome fits into the actual 3D structure of the nucleus and its functional compartments, how this varies in different cell states, and, ultimately, uncover new findings about how the nucleus and genome function in health and disease.

“We’re really excited to be a part of this interdisciplinary, iterative scientific effort,” Rafelski said. “You need this kind of integrative and holistic approach to address such a big question: What are the rules that connect nuclear organization and function?”

Ed Lein, Ph.D., Senior Investigator at the Allen Institute for Brain Science, is leading a project that is part of the “Center for Integrated Multi-modal and Multi-scale Nucleome Research,” headquartered at the University of California San Diego and led by Bing Ren, Ph.D., professor of cellular and molecular medicine. This project aims to study the nuclear organization in brain cells across development in both the laboratory mouse models and in humans with the goal to better understand the 3D organization of the mammalian genome. Lein and his Allen Institute for Brain Science colleagues will develop experimental and computational tools to understand how genome organization varies in different brain cell types and across species.

Research described in this article is supported by the National Human Genome Research Institute of the National Institutes of Health under Award Number UM1HG011585. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.