3D structure of DNA
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Cancer cells reorganize the 3D structure of their DNA

Scientists from Switzerland have used a new algorithmic method to study how cancer cells reorganize the 3D structure of their DNA in order to increase the activity of oncogenes. The researchers focused mainly on chromosomes and how they are organized in the tight space of the cell nucleus. They also explained how changes in histone proteins trigger the arrangement of chromatin regions in the cell nucleus.

Cancers are often very difficult to diagnose and treat. Cancer cells multiply uncontrollably, forming entirely new tissues called tumors. Numerous biological disorders occur: drastic changes in molecular processes and gene mutations, or changes in the genetic code of DNA. Many elements then fail to function properly at various levels.

There’s a reason scientists focus on the genome, which is where all cancers begin. If we understand what happens at the DNA level, perhaps one day we will be able to not only treat cancer, but also prevent it.

In a collaboration between Swiss researchers at the Federal Polytechnic University of Losanne (EPFL) and the University of Lausanne (UNIL), a new algorithmic method has been used to understand how cancer cells change the three-dimensional structure of their DNA when they increase the activity of oncogenes.

The research focuses on the chromosomes in which our DNA is encapsulated, and their organization in the tight space of the cell nucleus. Each of our body’s cells has about two meters of DNA, and our body stores it properly by wrapping it around histone proteins, like string wound around a yo-yo.

And this well-protected and protected complex of DNA along with the histone proteins is chromatin. Several chromatin make up the structure of chromosomes. Every normal cell has 23 chromosomes and two copies of each chromosome, and in cancer cells, their structure and organization are altered. For example, a fragment of a copy of chromosome 8 may be fused to a copy of chromosome 14. The chromosome may take on a more loose or compact structure, depending on chemical changes called “epigenetic marks.”

A group of scientists studied how changes in specific epigenetic marks alter chromosome structures and the expression of oncogenes that affect cancer growth.

Swiss researchers at the University of Lausanne developed a new algorithmic approach called Calder (after the American sculptor Alexander Calder) to get a good understanding of the distribution of genomic regions in the cell nucleus. Calder’s method was used to compare the spatial organization of the genome in more than 100 samples.

This arrangement is not static and, like Alexander Calder’s moving sculptures, can rearrange its elements. The researchers used Calder to detect regions of chromatin that had “shifted” from one area of the nucleus to another due to changes in epigenetic marks (that is, marks responsible for gene expression).

Meanwhile, a team of researchers at EPFL used Caldera to detect changes in 3D chromatin structure in normal cells and B-cell lymphoma cells. They also discovered that in lymphoma cells, specific epigenetic changes lead to repositioning of chromatin regions in different areas of the nucleus, resulting in new local interactions that in turn overactivate the expression of oncogenes.

The group of researchers also discovered that when two fragments of different chromosomes are interrupted and swapped, they adopt a three-dimensional (3D) structure that differs from normal copies. Importantly, these changes in 3D structure correspond to different epigenetic markers and induce high expression of genes that promote cancer cell growth.

For most of the time, scientists imagined human DNA as a long, linear molecule. And only recently have they begun to understand how its three-dimensional (3D) organization changes in cancer cells. Considering the spatial organization of DNA in the nucleus sheds new light on how cancer cells arise and how therapeutic modulation of epigenetic marks can block tumor growth.

These findings are described in the articles:
1. „Histone acetylation dynamics modulates chromatin conformation and allele-specific interactions at oncogenic loci” published in the journal Nature Genetics, 10.05.2021
(Sungalee S., Liu Y., Lambuta R. A., Katanayeva N., Collier M. D., Tavernari D., Roulland S., Ciriello G., Oricchio E.)
DOI: 10.1038/s41588-021-00842-x
2. „Systematic inference and comparison of multi-scale chromatin sub-compartments connects spatial organization to cell phenotypes” published in the journal Nature Communications, 10.05.2021
(Liu Y., Nanni L., Sungalee S., Zufferey M., Tavernari D., Mina M., Ceri S., Oricchio E., Ciriello G.)
DOI : 10.1038/s41467-021-22666-3
Translation was done with the assistance of DeepL translator.