Study Reveals Genome's Resilience and Vulnerability Without Cohesin
A study by researchers at Weill Cornell Medicine has found that temporarily disabling the cohesin protein complex in mouse embryonic stem cells severely disrupts the three-dimensional structure of the genome. However, most genes continued to function normally. The research, published on April 13 in the journal Nature Genetics, identified a small, specific group of developmentally important genes that failed to activate properly without cohesin when cells were directed to differentiate.
Background and Research Context
The cohesin protein complex is known to shape the three-dimensional organization of DNA inside a cell's nucleus. This structural role helps compact DNA to fit within the nucleus and facilitates contact between genes and distant regulatory elements that control their activity.
Previous research had suggested that removing cohesin had minimal effect on overall gene expression, creating a paradox given that mutations in the cohesin complex are commonly found in certain cancers and developmental disorders known as cohesinopathies.
Experimental Methodology
The research team, led by senior author Effie Apostolou, associate professor of molecular biology in medicine, studied mouse embryonic stem cells, which have the potential to develop into many different cell types.
To test cohesin's role under challenging conditions, the complex was removed immediately after cell division. This is the point when a cell must rebuild its entire genome architecture and gene expression program. First author UkJin Lee, a graduate student, performed the experiments and computational analysis.
The team used techniques that map DNA interactions in three dimensions to observe structural changes. They then tested both the maintenance of stem cell identity and the process of differentiation into specialized cell types.
Key Findings
Structural Disruption: The removal of cohesin severely disrupted the overall three-dimensional genomic architecture. Most DNA loops, which are formed by cohesin, failed to re-form after cell division.
Resilient Gene Activity: Despite this major structural disruption, the activity of most genes was largely unaffected. This was particularly true for genes involved in maintaining stem cell identity. The researchers described this as evidence of a "resilient molecular memory" that persists through cell division.
Vulnerable Genes During Differentiation: When the stem cells were guided to differentiate into specialized cell types, a small group of developmentally important genes failed to activate properly without cohesin. According to the study, these vulnerable genes often encode transcription factors, which are proteins that direct cell identity.
Mechanism of Vulnerability: The research indicates these specific genes are often located in isolated regions of the genome and rely on the cohesin complex to bring them into physical contact with distant DNA elements that enhance their activity.
Research Statements and Interpretations
In a statement, senior author Effie Apostolou said the goal was to "test this paradox under the most challenging conditions." First author UkJin Lee stated the findings on stem cell gene activity "point to a resilient molecular memory that persists through cell division."
Regarding the vulnerable genes, Apostolou noted they "tend to be developmentally important" and suggested that "the unique vulnerability of these genes to cohesin loss might have long lasting effects on proper development and differentiation." The researchers stated that inhibiting the long-range interactions facilitated by cohesin could derail normal development.
Future Research Directions
The research team stated they will continue to investigate why some genes are dependent on cohesin for proper activation while others function normally without it. A stated goal is to identify genes vulnerable to cohesin loss and assess how even slight perturbations in their activity could contribute to conditions like cancer or developmental impairment.
Publication and Funding
The study was published on April 13, 2023, in Nature Genetics. The research was funded by the Tri-Institutional Stem Cell Initiative by the Starr Foundation, the National Institute of General Medical Sciences, the National Institute of Neurological Disorders and Stroke, the Human Genome Research Institute, and the National Cancer Institute.