PROVIDENCE, R.I. [Brown University] — A new five-year, $10 million grant from the National Institutes of Health will enable Brown scholar and molecular biologist Nicola Neretti to serve as co-investigator for a multi-institution research center studying how cell structures affect functions in health and disease.

The researchers aim to develop fundamental knowledge to provide new insights into the role that the three-dimensional organization of cell nuclei plays in developmental disorders, aging and other cell processes. The effort is funded through the 4D Nucleome (4DN) program of the NIH’s Common Fund.

Based at Carnegie Mellon University, the center will also include researchers at the University of California, Los Angeles; the University of Illinois; Harvard Medical School; San Diego Biomedical Research Institute; the Allen Institute for Cell Science; the University of Dundee; and the National Cancer Institute.

“There’s no way at this level to have all these experts in one single lab,” said Neretti, an associate professor of Molecular biology, cell biology and biochemistry and member of Brown’s Center for Computational Molecular Biology. “So it’s notable that we’re able to collaborate with such a great group with very diverse expertise.”

A growing body of research shows that the cell nucleus is highly compartmentalized, and that this spatial phenomenon relates to cell function. But scientists don't yet understand how nuclear bodies tug and tether with chromosomes that carry genetic code, as well as other biomolecules such as RNA and proteins.

In his lab at Brown, Neretti studies cell senescence — when cells are unable to divide and become subject to damage, which plays a critical role in aging, inflammation and disease. He says the grant will use genomics and imaging to develop a better understanding of the structure of cell nuclei and how changes in that structure affect cell functions both in healthy individuals and in disease.

Jian Ma, the lead principal investigator of the new center and an associate professor in Carnegie Mellon’s computational biology department, said the spatial organization of chromosomes in the nucleus is critical, but scientists don’t yet have a complete picture of it.

Using a super-resolution microscope — which enables imaging at the nanoscale —  at Brown, Neretti will support the 4DN Center by imaging the structure of chromosomes in the nucleus. The images will capture the organization of chromosomes as well as high-resolution details of how chromosomes fold at specific loci.

“I come from computational biology and genomics, but we’re seeing more and more microscopy becoming this tool that can’t exactly replace genomics, but can do many of the things we’d want to do with genomics,” Neretti said. “By definition, microscopy is doing single-cell studies, while genomic studies look at thousands of cells. But with microscopy, you can see localization of what you’re targeting within the cell. My take is that this will become a more prominent tool, even for people who come from a genomics background.”

Ma said the 4DN Center’s plan is to generate “multimodal” data — for example, imaging paired with genomic data — and to develop machine learning algorithms and integrative structure models to make sense of that data. The goal is to find causal relationships between large-scale spatial genome structure and genome function, such as gene transcription and DNA replication.

Once assembled, those multimodal data sets, including the multiscale navigable reference maps of nuclear organization — and the new computational tools and visualization platform created to make sense of them — will be made widely available to the research community.

“We’ll be able to develop probes that can be utilized in other studies down the line to study cells and tissues,” Neretti said. “And hopefully, this will allow us in the future to rely on these kinds of collaborations to perform studies beyond just this grant.”

This work is supported by the NIH under award number 1UM1HG011593.