Epigenetic Changes May Cause Chromatin Repositioning

A team of researchers from EPFL and the University of Lausanne have used a novel algorithm-based method to study how cancer cells reorganize the 3D structure of their DNA in order to ramp up the activity oncogenes. They found that epigenetic changes can cause chromatin to be repositioned within the nucleus, leading to over-activation of oncogene expression. Their work was published in two journals, Nature Genetics and Nature Communications.

The researchers investigated how changes in specific epigenetic marks modify chromosome structures and the expression of genes that promote tumor growth, known as oncogenes. The team developed a novel algorithmic approach called Calder (after the American sculptor Alexander Calder) to track how genomic regions are positioned with respect to each other in the nucleus. 

"We used Calder to compare the spatial organization of the genome in more than a hundred samples," says lead researcher Giovanni Ciriello. "But this organization is not static and, just like Alexander Calder's mobile sculptures, it can rearrange its pieces." The researchers used Calder to track regions of chromatin that moved from one area of the nucleus to another as a result of changing epigenetic marks.

Meanwhile, the collaborating team at EPFL used Calder to track changes of the chromatin 3D structure in normal and B-cell lymphoma cells. They discovered that in the lymphoma cells, specific epigenetic changes cause chromatin regions to be repositioned in different areas of the nucleus, which can lead to novel local interactions that over-activate the expression of oncogenes.

They also found that when two fragments from different chromosomes are broken off and swapped, they assume a 3D structure that is distinguishable from the normal copies. Importantly, these changes of 3D structure correspond to different epigenetic marks, and induce high expression of genes that support tumor cell expansion. "Most of the time we think of our DNA as a long, linear molecule, and it's only recently that we started to understand how its 3D organization is altered in cancer cells," says co-author Elisa Oricchio. "Considering the spatial organization of DNA in the nucleus provides a new lens to understand how tumor cells originate, and how therapeutic modulation of epigenetic marks can block tumor progression."