Severance Hospital researchers uncover how cells choose between survival and death under stress

Severance Hospital announced that a research team led by Prof. Kim Hyung-pyo of the Department of Tropical Medicine at Yonsei University College of Medicine and research assistant Joo Jeong-sik of the Yonsei Institute of Biomedical Science has identified how ATF4 and CHOP — key regulatory proteins in the cellular stress response — activate enhancers, the regulatory regions of genes, and form three-dimensional connections between those enhancers and their target genes, playing a critical role in determining a cell's fate.

The findings were published in the international journal Nucleic Acids Research (impact factor: 15.0).

Cells in the human body are constantly exposed to stress from a range of sources, including nutrient deficiency, inflammation and toxic substances. When problems arise in the endoplasmic reticulum — the organelle responsible for producing and processing proteins — misfolded proteins accumulate, a condition known as endoplasmic reticulum (ER) stress.

Faced with such conditions, cells first activate defense mechanisms to repair damage and survive. But when stress is severe or prolonged, they abandon recovery and initiate a process of self-destruction. This response is closely linked to the onset and progression of a wide range of diseases, including cancer, diabetes, neurodegenerative disorders and liver disease.

What has remained unclear, however, is which genes promote cell survival, which trigger cell death, and how gene regulation drives cells toward such different fates.

The study is significant because it analyzed the cellular stress response not merely as a change in gene expression, but as a three-dimensional structural reorganization in which regulatory regions and target genes physically connect inside the nucleus. The team showed that whether ATF4 and CHOP act together determines whether a cell takes a survival path — tolerating damage — or a death path.

Going beyond conventional approaches that examine only gene expression, the team comprehensively analyzed the activation of gene regulatory regions, the binding of stress-response proteins, and the three-dimensional connections that form between genes and their regulatory regions inside the nucleus.

The researchers first induced ER stress in human cells, then tracked changes in gene expression and genomic structure. They found widespread activation of enhancers — regulatory switches that control gene activity — and extensive formation of close physical contacts between those enhancers and their target genes. Although enhancers are located far from their target genes along the DNA strand, the folding of DNA inside the nucleus brings them into proximity, amplifying gene activity.

The team confirmed that ER stress substantially alters the connections between these regulatory switches and their target genes.

The researchers then compared the functions of several proteins involved in the stress response. They found that ATF4 plays a central role in switching on regulatory elements and establishing connections between those switches and target genes under stress conditions.

CHOP, another protein in the pathway, selectively modulated a subset of the responses driven by ATF4. While ATF4 activates the cell's overall stress-response machinery, CHOP specifically amplifies the activity of genes associated with cell death.

By contrast, some genes required for cell survival — such as those that transport amino acids into the cell — were activated by ATF4 even in the absence of CHOP. This allowed the team to distinguish two branches of the ATF4-driven stress response: an adaptive survival response and a cell-death response, determined by whether CHOP is involved.

"This research explains, from the perspective of three-dimensional genomic structure, how cells can choose different fates even when exposed to the same stress signal," Kim said. "We expect these findings to serve as a foundation for developing treatment strategies — strengthening survival responses in diseases where cells need to be protected, and conversely promoting cell death in cases like cancer where targeted cell elimination is the goal."

The research was supported by the Mid-Career Researcher Program and the Bio and Medical Technology Development Program of the National Research Foundation of Korea, funded by the Ministry of Science and ICT, as well as by the SCL internal research fund of Yonsei University College of Medicine.