For a long time, the structure of the nucleus has been a visible clue to cell health or disease-affected. Although scientists have made significant progress in understanding genes and their functions, it is difficult to connect what we see under a microscope with what is happening in DNA. Now, a new approach helps bring these two worlds together.
Dr. Jason Buenrostro of Harvard University and researchers Ajay Labade, Dr. Zachary Chiang, and researchers at Harvard University, have created a new technology called “Extended Ins Intu Genome Sequencing (EXIGS)” that involves sequencing DNA directly within cells while preserving its natural structure. The study was published in the journal Science.
Exigs enables researchers to view DNA and important proteins (the control center of cells) in detail. Unlike earlier technologies, the technology allowed scientists to actually understand how these molecules line up in space and how they interact. The team used this method to study cells in people with Hutchinson-Gilford Progeria syndrome (HGP), a rare disease that causes children to age rapidly.
They found an unexpected connection between the abnormal shape of these nuclei and the silencing of certain genes. In healthy cells, asterin is a loose and active form of DNA that opens genes and keeps the cells function properly. But in progeny cells, this active DNA was found to be turned off in certain regions. This suggests that changes in the shape of the nucleus may be enough to turn off important genes.
“The abnormality of layer fixation is associated with hot spots of abnormal concurrent inhibition that may erode the identity of a cell,” said Dr. Buenrostro. Laminin forms part of the support shell of the nucleus. This means that when such supportive structures collapse, the genes that confer unique effects on the cells may be silenced.
To confirm the reliability of its method, the researchers showed that Exigs kept the natural structure of the nucleus intact while providing clearer details, ten times more than earlier sequencing methods. They bind it with fluorescent markers, which is a way to make specific molecules glow so that they can be tracked to see how chromosomes (the structures that hold DNA) move and how these changes are linked to gene activity.
“The presence of layers of abnormalities is associated with an increase in the frequency of neighborhood disruptions,” Dr. Labade said, noting that although these abnormalities are significantly associated with changes in gene activity, they do not drag white chromatin directly to them. Instead, the effect is more mottled and local, rather than evenly affecting the entire core.
Their observations suggest that even in a single cell, the regions affected by these structural changes are unpredictable. These problem spots are scattered together and tend to affect the region of the genome (intact genetic material), involved in communication between cells. This randomness may make the effect more difficult to resolve.
Dr. Chiang reviews the years of efforts to get to this point: “This project was initially a crazy idea: we could sequence the genome inside the nucleus directly. Apart from academia, it will fly anywhere, and it took us seven hard years to achieve reality.” He also reflects on the importance of continuing to fund this high-risk, advanced science. Although the project received the highest score in the national research funding competition, the project suddenly gained support due to wider political issues affecting the scientific budget.
The new tool has a far greater significance than a disease. Exigs is for exploring how changes in the shape and structure of the nucleus play a role in aging, cancer and many other conditions. It provides a way to ultimately link what we see under a microscope to how genes behave.
Journal Reference
Labade AS, Chiang ZD, Comenho C., Reginato PL, Payne AC, Earl AS, Shrestha R., Duarte FM, Habibi E., Zhang R., Church GM, Boyden ES, Chen F., Buenrostro JD “Expansion in situ genome sequencing links nuclear abnormalities to hotspots of aberrant euchromatin repression.” Biorxiv, 2024. Doi:
About the Author
Dr. Jason Buenrostro He is a leading researcher in the fields of gene regulation and single-cell genomics. Located at Harvard University and the Extensive Institute, he pioneered the development of several technologies that reveal how cells organize and regulate their DNA, including the widely adopted ATAC-SEQ method. His work focuses on developing technologies that link the spatial arrangement of the genome to its functional state, with the goal of understanding how these processes go wrong in diseases such as cancer and aging. Dr. Buenrostro is deeply committed to training the next generation of scientists and promoting an open and innovative research environment. His interdisciplinary approach bridges molecular biology, bioengineering and computational science.
Dr. Zack Chiang is a genomics researcher known for his contribution to spatial genomic analysis and high-resolution DNA mapping in individual cells. As a scientist at Harvard University and the Broad Institute, he played a key role in the development of expanding in situ genome sequencing (EXIGS), a method that visualizes DNA and nucleoproteins with nanoscale accuracy. His research interests lie in the intersection of technological development and biological discovery, especially how physical changes in cells affect gene activity. Dr. Chiang is also an advocate for strong academic funding and transparent research practices. He recently announced that he left academia and reflected on the challenges of long-term projects that continue to be ambitious in the scientific landscape.
Dr. Ajay Labade It is a molecular biologist and technological innovator who specializes in genome sequencing and spatial cell analysis. He co-developed Exigs, a novel approach that allows scientists to study the physical and functional organization of the genome intact cells. Dr. Labade is strongly focused on basic science and rigorous experimental nature and has spent years linking microcellular structures to large-scale genetic patterns. His method combines wet and LAB experiments with advanced imaging and computational modeling. Dr. Labade is a strong belief in the power of curiosity-driven science, emphasizing the importance of academic freedom and long-term investment in high-risk, high-return research.
Caroline Comenho He is a rising scientist in the field of cell genomics and has made a significant contribution to the development of high-resolution genome sequencing technology. At the Broad Institute and Harvard University, she collaborated on the Exigs platform, which allows precise DNA spatial mapping within the nucleus. Her work focuses on understanding how the structure of the nucleus affects gene expression, especially in aging and disease-related diseases. Commenho combines molecular biology expertise with a strong foundation of imaging technology to help bridge the gap between sequencing data and visual cell characteristics. She represents new researchers driven by technological innovation and biological insights.
