The way our DNA is organized within cells isn’t static, but constantly changing, according to a latest study. These three-dimensional shifts influence gene activity and may play a role in the development of cancer and neurodevelopmental conditions, including autism spectrum disorder.
Nearly two meters of DNA must be compacted into each human cell’s microscopic nucleus. This organization isn’t rigid. Research conducted by researchers at the Salk Institute for Biological Studies shows that DNA loops continuously form and dissolve, driven by organizing proteins – protein complexes like cohesin – and that different regions of the genome change structure at distinct speeds. Understanding how DNA is organized is crucial, as disruptions in this process can contribute to disease.
The genome contains approximately six billion base pairs and tens of thousands of genes. To fit within the nucleus and remain accessible when needed, DNA forms loops. These loops are generated by a protein complex called cohesin, assisted by the protein NIPBL, which helps cohesin move along the DNA and shape these structures.
“The human genome contains approximately six billion base pairs, and over the last decade we’ve begun to better understand the molecular mechanisms that fold and organize this enormous amount of information,” said in a statement Dr. Jesse Dixon, associate professor and holder of the Developmental Chair at Salk, whose research focuses on how DNA is folded and organized within the cell nucleus. “Errors in this structural organization can contribute to cancer and neurodevelopmental disorders, including autism spectrum disorder.”
“Interestingly, this folding of DNA doesn’t happen once, after which the genome remains unchanged, but appears to unfold continuously, through repeated processes of disassembly and reconstruction. Our study provides a clearer picture of where and how frequently these reorganizations occur, which helps us better understand how these molecular mechanisms perform and, what can happen when they are affected in cancer or developmental disorders,” he explained.
Dr. Jesse Dixon used human induced pluripotent stem cell (iPSC)-derived cardiomyocytes to demonstrate that the way DNA is folded and continuously reorganized within the cell nucleus influences cell identity – the set of active genes that determine the function and specific characteristics of each cell type. Credit: Salk Institute
Previous research has shown that the loops formed by cohesin aren’t permanent, but repeatedly form (fold) and dissolve. The research team analyzed how frequently these changes occur and whether certain regions of the genome are more dynamic than others.
To do this, the researchers reduced the level of the NIPBL protein in immortalized human retinal pigment epithelial cells (RPE-1) – cells derived from the retinal pigment epithelium that have been adapted to continuously multiply in culture, being stabilized for research.
In the absence of NIPBL, cohesin moved more slowly along the DNA and formed fewer loops, and the genome began to unravel. This process wasn’t uniform. Some regions relaxed quickly, even as others changed gradually, over several hours.
The speed of these changes correlated with the activity of genes in those regions. Stable loops, which persisted for hours, were identified in areas where genes were inactive.
Conversely, loops that formed and dissolved rapidly were associated with regions where genes were active and involved in functions characteristic of each cell type.
Immortalized human retinal pigment epithelial cells (RPE-1) undergoing division, illustrating the remarkable ability of the organism to compact, store, duplicate, and reorganize long molecules of genetic material (DNA). Credit: Salk Institute
“One thing these results seem to indicate is that the continuous folding and unfolding of the genome may be particularly important to help the cell ‘remember’ what type of cell it needs to be, by maintaining the expression of genes specific to each cell type,” researchers noted.
To evaluate the impact on cell identity, the team studied heart cells and neurons obtained from human induced pluripotent stem cells (iPSCs). Dynamic folding was found to be particularly important in genomic regions containing genes essential for cardiac function and neuronal function, respectively.
Because these specialized genes occupy different positions in the genome, the DNA’s ability to repeatedly modify its three-dimensional organization may help each cell type maintain its own genetic activity program.
The research team at Dr. Jesse Dixon’s laboratory used neurons derived from human induced pluripotent stem cells (iPSC) to show that the way DNA is folded and continuously reorganized within the nucleus influences cell identity. Credit: Salk Institute
The authors suggest that genomic regions involved in defining cell identity are more dynamic because DNA loops repeatedly form and dissolve in these areas, maintaining contact between genetic sequences that need to communicate with each other. By constantly recreating these contacts, the cell can continue to activate the genes needed to produce proteins specific to its function.
The findings provide an explanation for the widespread effects of defects in genome folding.
Mutations in the mechanisms responsible for three-dimensional organization may be associated with conditions such as Cornelia de Lange syndrome, which affects multiple organs and systems. This rare genetic disease, present from birth, affects physical and intellectual development.
Cornelia de Lange syndrome is characterized by growth delay, distinctive facial features, limb malformations, and varying degrees of cognitive difficulty. The condition is associated with mutations in genes involved in organizing and regulating DNA inside the cell.
In the case of cancer, the authors suggest that altering the processes of organization and reorganization of the genome in space could alter cell identity and contribute to excessive cell division, a hallmark of tumor development.
Confirming that how DNA is packaged and reorganized within the nucleus directly influences gene regulation opens new avenues for developing therapeutic strategies to correct defects in genome organization associated with cancer and developmental diseases.
The study was published in the journal Nature Genetics.
