Researchers have uncovered the genetic regulatory mechanism that determines whether a cell will survive or self-destruct when under stress.
Severance Hospital announced on Friday that a research team led by Professor Kim Hyung-pyo from Yonsei University College of Medicine and Assistant Researcher Joo Jeong-sik from the Yonsei Institute of Life Science has made a groundbreaking discovery. They found that key regulatory proteins ATF4 and CHOP activate genetic regulatory regions called enhancers, forming crucial three-dimensional connections between enhancers and genes that play a pivotal role in determining cell fate.
The body’s cells are constantly bombarded by stressors such as nutrient deficiency, inflammation, and toxic substances. When the endoplasmic reticulum – a cellular organelle responsible for protein synthesis and folding – malfunctions, misfolded proteins accumulate, leading to endoplasmic reticulum stress.
In response to such stress, cells initially activate defense mechanisms to repair damage and ensure survival. However, if the stress is severe or prolonged, cells may opt for programmed cell death. This stress response is intricately linked to the development and progression of various diseases, including cancer, diabetes, neurodegenerative disorders, and liver diseases.
While previous research focused on identifying which genes are activated or suppressed during endoplasmic reticulum stress, it remained unclear how specific genes influence cell survival or death, and how these genes are regulated to determine different cellular fates.
The research team employed a comprehensive approach, analyzing not only gene expression but also the activation of genetic regulatory regions, binding of stress response proteins, and three-dimensional connections formed between genes and regulatory regions within the nucleus.
They began by inducing endoplasmic reticulum stress in human cells and observing changes in gene expression and genomic structure. Their findings revealed widespread activation of enhancers – genetic regulatory switches – and the formation of connections between these enhancers and their target genes.
Enhancers function as molecular switches that regulate gene activity. Although physically distant from their target genes on the DNA strand, they interact with genes through DNA folding within the nucleus, enhancing gene activation.
The team discovered that these gene-enhancer connections undergo significant changes during endoplasmic reticulum stress.
Further investigation into the functions of various stress response proteins revealed that ATF4 plays a central role in activating genetic regulatory switches and establishing gene-enhancer connections during stress.
In cells lacking ATF4, many stress-responsive regulatory regions failed to form proper connections with their target genes.
Another protein, CHOP, was found to selectively regulate a subset of ATF4-mediated responses. While ATF4 activates the cell’s overall stress response system, CHOP specifically enhances the activity of genes related to cell death.
Interestingly, some genes crucial for stress tolerance, such as those involved in amino acid transport, remained functional through ATF4 even in the absence of CHOP. This finding allowed researchers to distinguish between adaptive survival responses and cell death responses based on ATF4-CHOP cooperation.
The team also conducted experiments to directly inhibit genetic regulatory switches and visualized the physical proximity between genes and regulatory switches within the nucleus, confirming the essential role of these three-dimensional connections in gene activation.
This study reveals that cellular stress response involves more than simply turning genes on or off. Instead, cells adjust three-dimensional connections between genes and regulatory switches within the nucleus to fine-tune genetic programs for survival or death.
Professor Kim explained that this research elucidates how cells can choose different fates even when exposed to the same stress signals, from the perspective of three-dimensional genome organization. It anticipates that this foundational work will contribute to developing novel therapeutic strategies – enhancing survival responses in diseases requiring cell protection and promoting cell death in conditions like cancer where cell elimination is necessary.
The findings were published in the prestigious international journal Nucleic Acids Research (Impact Factor 15.0). This study was supported by the Ministry of Science and Information and Communications Technology (ICT) through the Korean Research Foundation’s Mid-Career Research and Bio-Medical Technology Development Program, as well as internal research funding from Yonsei University College of Medicine.