Two to three metres of DNA can fit inside a single cell, thus it can only be stored by being wound tightly into coils. The answer is chromatin, a compound of DNA encased in histone-like proteins. This complex gradually folds into the multi-layered arrangement of loops, domains, and compartments that we know as chromosomes in the 3D world. Any issues with chromatin structure can have negative implications, including the emergence of cancer because the architecture of chromatin is directly linked to gene expression and the proper functioning of the cell.
A common event in around 30 per cent of all human cancers is “whole genome doubling” (WGD), whereby the entire set of chromosomes in a cell is duplicated. WGD leads to genomic instability inside the cell, which can result in chromosomal alterations and other mutations that contribute to the development of cancer.
Now, a team of researchers led by Elisa Oricchio at EPFL and Giovanni Ciriello at UNIL, has uncovered a new clue as to how WGD drives cancer. In a study published in Nature, the scientists show that WGD can affect the 3D organization of the chromatin inside the cell through a phenomenon called “loss of chromatin segregation”.
The researchers looked at cells that lack the tumor suppressor gene p53, making them prone to WGD. They found that WGD leads to a reduction in the segregation of chromatin’s structural elements, such as loops, domains, and compartments, upending its careful organization in the cell.
The result is a mixing of genetic material that is normally kept separate, changing the position of genomic regions in the 3D space, known as “sub-compartment repositioning.” This sets the stage for the activation of oncogenes, which are genes that contribute to the development of cancer.
The researchers also found that the effects of WGD on chromatin organization are largely independent of chromosomal alterations, meaning that loss of chromatin segregation and chromosomal instability are complementary mechanisms that work together to promote cancer development. (ANI)
