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Six feet. Two meters. This is the length of DNA we have in each one of our cells. That’s almost the height of Michael Jordan! But those six feet of DNA need to fit into a tiny space that is between 5-10 micrometers. To put it into perspective, that’s like 24 miles of thread fitting inside one tennis ball! How do our cells do this? What are the implications when our DNA doesn’t fit correctly in our cells?
We are finally beginning to realize that our DNA isn’t randomly crammed into the cell. Rather, our DNA is precisely organized into different areas – or “neighborhoods” (different colored blobs in A). This organization is extremely important, as it brings parts of our DNA close together to help activate and express genes in the right place, at the right time. In the figure to the right, C gives us a closer look as to how neighborhoods help regulate gene expression. Genes are blue arrows, green ovals help turn on genes, and the pink hexagons insulate, or separate, this genetic neighborhood from others. When these neighborhoods aren’t correctly separated, genes aren’t expressed in the right place and at the right time, and diseases and cancers can arise. Ultimately, we still don’t fully understand how a cell knows exactly how to organize it’s DNA and therefore we don’t understand what the different DNA neighborhoods are in cancer cells.
A recent paper, published in Science Advances in January 2020, used mathematical modeling and experimental data to try to understand how DNA neighborhoods are formed and maintained under stress. They combined electron microscopy and live cell imaging to view in real time how the DNA is organized both in a normal state and under stress(stress can be anything from heat to diseases). Under stress, DNA is usually able to rearrange itself to adapt to the stressors such as heat. However, when the cell has mutations in the proteins that help with DNA organization and rearrangement (great s OncoBites article here), the cell doesn’t adapt as well, and rearrangements can be permanent, resulting in genes stuck in new or different neighborhoods, changing their expression levels and advancing disease.
A paper published in Genome Research in 2016 looked at how DNA neighborhoods were different in cancer cells compared to normal cells. They found that cancer genomes were still able to create neighborhoods, but the neighborhoods were smaller than in normal cells. This was because the cancer cells were creating new neighborhoods that weren’t in normal cells. These new neighborhoods are determined by boundaries (the pink hexagons in the image above); essentially anything between two boundary points (or pink hexagons) is a neighborhood. And if, within a neighborhood, another boundary point (pink hexagon) is added, that neighborhood has just split into two new neighborhoods. The genes that were properly expressed in the original neighborhood are now separated from each other, and could be expressed at different levels than before – changes that could result in or advance disease.
Therefore, understanding what regulates proper DNA organization will contribute to a more complete understanding of normal DNA neighborhoods and gene expression, as well as abnormal neighborhoods that form in diseases like cancer.
Edited by Gabrielle Dardis
- Huang, K., Li, Y., Shim, A. R., Virk, R. K. A., Agrawal, V., Eshein, A., . . . Szleifer, I. (2020). Physical and data structure of 3D genome. Sci Adv, 6(2), eaay4055. doi: 10.1126/sciadv.aay4055
- Sauerwald, N., & Kingsford, C. (2018). Quantifying the similarity of topological domains across normal and cancer human cell types. Bioinformatics, 34(13), i475-i483. doi: 10.1093/bioinformatics/bty265