Chromatin Organizes Itself Into 3D ‘Forests’ in Single Cells

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Knowledge could help scientists understand chromatin’s role in cancer, other diseases

Vadim Backman, PhD, a professor of Biomedical Engineering in Northwestern’s McCormick School of Engineering and of Biochemistry and Molecular Genetics at Feinberg, co-led the study that discovered how chromatin folds at the single-cell level.

A single cell contains the genetic instructions for an entire organism. This genomic information is managed and processed by the complex machinery of chromatin — a mix of DNA and protein within chromosomes whose function and role in disease are of increasing interest to scientists.

A Northwestern University research team — using mathematical modeling and optical imaging they developed themselves — has discovered how chromatin folds at the single-cell level. In the study published in Science Advances, the scientists found chromatin is folded into a variety of tree-like domains spaced along a chromatin backbone. These small and large areas are like a mixed forest of trees growing from the forest floor. The overall structure is a 3D forest at microscale.

Chromatin is responsible for packing DNA into the cell nucleus. In humans, that’s about six feet of DNA in each cell. The new work suggests that chromatin is more structured and hierarchical in single cells than previously thought. Learning how chromatin correctly operates will help scientists understand what goes wrong with it in cancer and other diseases.

“By integrating theoretical and experimental work, we have produced a new chromatin folding picture that helps us see how the 3D genome is organized at the single-cell level,” said Igal Szleifer, PhD, the Christina Enroth-Cugell Professor of Biomedical Engineering, in McCormick, and of Medicine in the Division of Pulmonary and Critical Care. He co-led the research team  Vadim Backman, PhD.

“If genes are the hardware, chromatin is the software,” said Backman, who is the Walter Dill Scott Professor of Biomedical Engineering in Northwestern’s McCormick School of Engineering and a professor of Biochemistry and Molecular Genetics, and of Medicine in the Division of Hematology and Oncology.

“If the structure of chromatin changes, it can alter the processing of the information stored in the genome, but it does not alter the genes themselves. Understanding chromatin folding holds the key to understanding how cells differentiate and how cancer happens.”

Advances in genomic, imaging and information technologies are just beginning to enable scientists to better understand how chromatin works. The Northwestern investigators used a partial wave spectroscopic  microscope, optical imaging developed by Backman and colleagues, to peer deep into live cells and “sense” alterations in chromatin packing. They also used electron imaging.

“Our paradigm-shifting picture of chromatin folding is an important missing piece in the holistic view of genomic structure,” said Kai Huang, the study’s first author. Huang is a postdoctoral fellow in Szleifer’s research group. “The results should inspire new strategies to fight cancer.”

The research was supported by the National Science Foundation and the National Cancer Institute at the National Institutes of Health.

Backman is also associate director for research technology and infrastructure at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University and a member of the Chemistry of Life Processes Institute; Szleifer is also a member of the Lurie Cancer Center.