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Investigators at UMass Medical School have received two, five-year grants totaling $13 million to explore how the 4D genome structure influences gene expression, cellular function, development and disease as it reshapes itself over time. The Center for 3D Structure and Physics of the Genome, led by Job Dekker, PhD, will receive the bulk of the funding—approximately $11 million. Paul D. Kaufman, PhD, will receive $2 million to investigate the role of the nucleolus in human genome organization in normal and disease states.
The grants are part of the NIH’s 4D Nucleome Program, an interdisciplinary effort launched in 2015 comprising 30 research teams across the country with the goal of mapping the three-dimensional architecture of the human genome and how this organization changes over time—the fourth dimension. The goal is to understand how 4D genome structure influences gene expression, cellular function, development and disease.
“The first phase of the project revolved around developing new technologies and techniques that we could use to explore the structure of the genome in time and space,” said Dr. Dekker, Howard Hughes Medical Institute investigator, the Joseph J. Byrne Chair in Biomedical Research, professor of biochemistry & molecular pharmacology and co-director of the Program in Systems Biology. “This new center study will investigate how the genome folds across human lifespan starting from the early pluripotent stem cell state to later stages when cells age.”
Dr. Kaufman, professor of molecular, cell & cancer biology, said, “Bringing a wide variety of investigators into the consortium improves communication between a broader spectrum of researchers. This leads to new ideas and advances science in new, and sometimes unexpected, ways.”
Although DNA is composed of a linear sequence of bases, it doesn’t exist inside the cell nucleus in a simple, straight form. More like a ball of cooked spaghetti, the genome folds and loops back on itself so it can fit inside the tight confines of the nucleus. The shape it takes has a profound influence on which genes in a cell are turned on or turned off. This 3D architecture varies from cell type to cell type and even between cell states. To properly understand how the genome works to coordinate gene expression, it’s necessary to understand how and why the genome is organized in space.
Dekker is a pioneer in the study of the three-dimensional structure of the genome. He developed the chromosome conformation capture technologies, biochemical techniques for determining how DNA segments interact and are linked to one another, which are the heart of the “3C,” “5C,” “Hi-C” and “Micro-C” tools used by researchers worldwide to map the structure and organization of chromosomes inside cells.
Using new technologies developed during the first phase of the 4D Nucleome Program, Dekker and colleagues will examine how the shape of the genome changes as cells differentiate from pluripotent stem cells to hepatocytes through a series of intermediate differentiation states. He will observe that architecture as it matures from an immature state early in differentiation to a fully matured form in fully differentiated cells. The center will also study how the folding of the genome will deteriorate again later in life as cells age and eventually die. The group will focus on studying cells obtained from patients who suffer from the early-onset aging disease Hutchinson-Gilford progeria syndrome. In parallel to mapping the architecture of the genome using cutting edge genomic and imaging approaches across lifespan, the center will also investigate the molecules and proteins that cause the genome to fold and change its shape. For this, the group will use new subnuclear proteomics approaches developed by the Sontheimer lab during the previous phase of the project. Understanding how these mechanisms work will inform our ability to treat disease or mitigate the effects of cellular aging and stress.
Dekker co-leads the center with Leonid A. Mirny, PhD, professor of medical engineering & science and physics at the Massachusetts Institute of Technology. Also on board are Oliver J Rando, MD, PhD, professor of biochemistry & molecular pharmacology; Erik J Sontheimer, PhD, professor of molecular medicine; Rene Maehr, PhD, assistant professor of molecular medicine, all of UMMS; and Robert Goldman, PhD, professor of cell and development biology at Northwestern University; John Marko, PhD, professor of physics at Northwestern University; Anders S. Hansen, PhD, assistant professor of biological engineering at the Massachusetts Institute of Technology; Nils Gehlenborg, PhD, assistant professor of biomedical informatics at Harvard Medical School; and Andrew Stephen, PhD, assistant professor of biology at the University of Massachusetts Amherst.
Kaufman will investigate dynamic genome organization events at the surface of the nucleolus, the specialized nuclear body where ribosomes are made. In particular, his team found that centromeres, the sites where chromosomes are attached to spindles during cell division, frequently depart from the nucleolar surface in innate immune cells like macrophages when they sense hallmarks of infection. Collaborating with Kaufman are Daniel Foltz, PhD, associate professor of biochemistry and molecular genetics, and Sui Huang, MD, PhD, associate professor of cell and developmental biology, both at Northwestern University’s Feinberg School of Medicine. Those groups discovered similar rearrangements of centromere-nucleolus interactions comparing normal and cancer cells. Therefore, Kaufman and colleagues will compare the genomic shape between both healthy cells with cancerous cells, and also study changes during immune cell activation. Understanding the differences in how these cells are structured may have important implications for understanding how cancer cells divide more quickly than healthy cells, how they metastasize to other tissues, and how our immune system can be activated and de-activated.
The 4D Nucleome Program is funded out of the NIH Common Fund, which is managed through the office of the NID director. Common Fund programs address emerging scientific opportunities and pressing challenges in biomedical research that no single NIH institute or center can address on its own but are high priority for the NIH as a whole.
As part of this new round of funding, each awardee has set aside 20 percent of their budget from years two to five to develop new projects and collaborations among program members. This unreserved money will be used to stimulate new projects that arise during the life cycle of the grant. “The hope is that this will facilitate a real grassroots development of collaboration between labs and transform the program into a real network of labs all working together toward the same goal of understanding how the human genome works,” said Dekker.
Related stories on UMassMed News:
Job Dekker and colleagues develop new model to examine large mutations in cells
Job Dekker receives 2018 Edward Novitski Prize
Center for 3D Structure and Physics of the Genome established at UMMS
