Exploring the Impact of 3D Genome Structure on Gene Regulation

In a groundbreaking study published on June 27, 2025, in the journal Genome Biology, researchers from Sanford Burnham Prebys Medical Discovery Institute and their collaborators in Hong Kong have illuminated the critical role of the three-dimensional (3D) structure of the genome in regulating gene activity. The study, led by Dr. Kelly Yichen Li, a postdoctoral associate at Sanford Burnham Prebys, reveals how the arrangement of chromatin influences gene expression, with significant implications for understanding various diseases including cancer and developmental disorders.

Historically, educational models have depicted the human genome primarily in one dimension, focusing on the linear sequences of DNA that form genes. However, this oversimplification neglects the complexity of the genome's 3D architecture. According to Dr. Yuk-Lap (Kevin) Yip, a professor and interim director of the Center for Data Sciences at Sanford Burnham Prebys, “The 3D shape of genomic regions plays a crucial role in gene regulation.” This study underscores the importance of topologically associating domains (TADs)—specific regions of the genome that interact more frequently with one another while remaining isolated from adjacent areas.

The research team utilized advanced imaging techniques to map the spatial arrangement of chromatin within cells. They discovered that TAD-like regions often exhibit a globular shape, which influences the accessibility of genomic regions to biochemical signals. "If you picture these clumps of chromatin fiber being roughly in the shape of a potato, we predicted that regions of the genome closer to the surface are more active due to exposure to nearby biochemical signals in the cell nucleus," Dr. Yip explained. Their findings suggest that the structural characteristics of chromatin can dictate the activity levels of associated genes, with surface regions demonstrating higher activity than those buried deep within the chromatin mass.

The implications of these findings extend beyond basic biology. Approximately 12% of genomic regions in breast cancer cells show structural abnormalities in their chromatin, indicating a potential link between chromatin architecture and cancer pathogenesis. Dr. Li emphasized that disruptions in the 3D structure of the genome could lead to significant biological consequences, such as the development of T-cell acute lymphoblastic leukemia.

To quantify the influence of chromatin's 3D structure, the researchers developed a novel metric termed 'coreness,' which measures a genomic region's proximity to the center of a chromatin clump. By correlating this metric with gene activity, they aim to investigate how the spatial organization of chromatin relates to gene regulation and disease across various cell types.

As the research team continues to explore these dynamics, they plan to collaborate with Dr. Pier Lorenzo Puri, a physician-scientist, to further investigate the impact of 3D genome structure on muscle stem cell development and the progression of muscular dystrophy. This interdisciplinary approach highlights the interconnectedness of genomic structure and disease, paving the way for novel therapeutic strategies.

In conclusion, the study conducted by Dr. Li and her colleagues marks a significant advancement in our understanding of the genome's 3D structure and its role in gene regulation. As researchers unravel the complexities of chromatin architecture, the potential to develop targeted therapies for diseases linked to chromatin abnormalities becomes increasingly promising. The findings represent not just a fundamental shift in genomic research but also a crucial step toward innovative approaches in medicine and biotechnology.