Research Finds Cells Respond to Stress by Folding and Unfolding Their Genomes

Newswise — Finding that chromatin architectural proteins are redistributed as cells respond to stressors such as heat was not the expected outcome for Dartmouth's Giovanni Bosco, PhD and collaborator Victor Corces, PhD of Emory University. The paper, "Widespread Rearrangement of 3D Chromatin Organization Underlies Polycomb-Mediated Stress-Induced Silencing," was published as the cover story in Molecular Cell.

"Basic questions about how biology works, such as how cells respond to changes in their environment, still have great value and potential to impact fields of study far beyond what we are focusing on in the moment," said Bosco. "What makes this research exciting is that now we have clues as to what molecules are required for a robust heat stress response and how genome folding facilitates this cellular response. This is potentially applicable to cells under other types of stress like that induced by pathological conditions, or some sort of therapy."

Typically, genomes are massive in size and detecting changes in how entire genomes fold in 3D space has not been possible. The question of how, or even if, genomes change their structures under certain circumstances, such as stress, has remained unexplored.

Bosco and collaborators used a novel method to detect how frequently every single bit of the genome physically touches every other bit. This involves billions of interactions and, to organize the data, the investigators mapped the interactions and revealed the changes in touches based on altered amounts or types of stress. They discovered that genome folding is an essential part of a robust cellular response to stress from heat. Specifically, temperature stress induces movement of architectural proteins from the borders of genome structural domains to inside those domains as well as a dramatic reorganization of the 3D structure of the cell's nucleus. This results in weakening of borders and a corresponding increase in long-distance inter-chromosomal interactions.

Looking forward, uncovering cellular response to stress may provide Bosco with leverage to determine how to trick undesirable cells, such as cancer or damaged cells, into dying instead of recovering from stress.

Bosco is Associate Professor of Genetics at Dartmouth's Geisel School of Medicine. His work in cancer is facilitated by Dartmouth's Norris Cotton Cancer Center where he is a member of the Cancer Mechanisms Research Program.

"Widespread Rearrangement of 3D Chromatin Organization Underlies Polycomb-Mediated Stress-Induced Silencing" was supported by the National Institutes of Health grant RO1 GM069462 and generous funds from the Geisel School of Medicine.

About Dartmouth-Hitchcock Norris Cotton Cancer CenterNorris Cotton Cancer Center combines advanced cancer research at Dartmouth and the Geisel School of Medicine with patient-centered cancer care provided at Dartmouth-Hitchcock Medical Center in Lebanon, NH, at Dartmouth-Hitchcock regional locations in Manchester, Nashua, and Keene, NH, and St. Johnsbury, VT, and at 12 partner hospitals throughout New Hampshire and Vermont. It is one of 41 centers nationwide to earn the National Cancer Institute's "Comprehensive Cancer Center" designation. Learn more about Norris Cotton Cancer Center research, programs, and clinical trials online at cancer.dartmouth.edu.