Genome Architecture Disruption Selectively Impairs Developmental Genes

Researchers at Weill Cornell Medicine have identified how disrupting the three-dimensional architecture of the genome selectively impairs genes critical for development, according to a study published April 13, 2026, in Nature Genetics. The findings help resolve a long-standing biological paradox regarding how the organization of DNA affects cell function.

The study focused on the role of cohesin, a protein complex responsible for shaping the 3D structure of DNA inside the cell nucleus. Cohesin organizes DNA into loops, which allows the genome to fit within the nucleus and brings distant regulatory elements into contact with the genes they control. This process is essential for determining which genes are turned on or off, thereby maintaining the identity and function of a cell.

Resolving the Cohesin Paradox

For years, biologists faced a contradiction in their understanding of genome architecture. Previous research indicated that removing cohesin and the loops it creates had very little impact on overall gene activity. However, mutations in cohesin are frequently observed in various cancers and in disorders known as cohesinopathies, which cause cognitive and physical developmental impairments.

To investigate this discrepancy, the research team used stem cells in a specialized experimental system. They specifically examined the genome’s behavior immediately following cell division, a critical window when the entire architecture of the genome and the gene expression program must be reconstructed from scratch.

We wanted to test this paradox under the most challenging conditions: right after cell division, when the entire genome architecture and gene expression program must be rebuilt from scratch

Effie Apostolou, associate professor of molecular biology in medicine and member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine

Selective Impact on Developmental Genes

The researchers found that while temporarily disabling the cohesin complex drastically disrupted the genome’s 3D structure, the majority of genes continued to function normally. This explains why overall gene activity often appears unchanged even when genome architecture is compromised.

However, the study revealed that a small, specific group of genes is highly vulnerable to these disruptions. These affected genes play critical roles in guiding cells to differentiate into specific types, such as brain, liver, or heart cells.

The findings suggest that while most of the genome is resilient to the loss of architectural loops, the genes governing developmental trajectories are uniquely sensitive. Even slight perturbations in the activity of these specific genes can lead to profound biological consequences.

Implications for Cancer and Developmental Disorders

By identifying the vulnerability of developmental genes to cohesin loss, the study provides new insights into the mechanisms behind certain cancers and developmental disorders. The researchers intend to continue pursuing the study of genes that are particularly susceptible to the loss of cohesin.

The research team aims to assess how minor changes in the activity of these vulnerable genes contribute to the onset of cancer or the manifestation of developmental impairments. This understanding of the interplay between genome architecture and gene expression may offer a path toward better understanding the molecular basis of cohesinopathies.