Human cancers often experience whole genome duplication (WGD), which promotes chromosomal instability and the development of aneuploidies.
A team of EPFL researchers led by Elisa Oricchio and Giovanni Ciriello discovered a new clue about (WGD). Whole genome duplication is a recurrent event in human cancers that allows cancer to develop. WGD changes the arrangement of DNA in 3D space and activates oncogenes that promote cancer growth.
Chromatin is a complex of DNA wrapped around histone proteins that make up the chromosomes. This complex gradually folds into a multi-layered organization consisting of loops, domains, and compartments in 3D space, which we call chromosomes. Because chromatin structure is so closely linked to gene expression and cell function, problems with chromatin structure can have serious consequences, including the development of cancer.
“Whole genome duplication” (WGD) is a common event in about 30% of all human cancers, where a cell’s entire set of chromosomes is duplicated. WGD causes genomic instability in the cell, which can result in chromosomal changes and other mutations that contribute to cancer development.
WGD causes genomic instability in the cell, which can result in chromosomal changes and other mutations that contribute to cancer development.
Researchers found that WGD could affect the 3D organization of chromatin in the cell via a phenomenon known as “loss of chromatin segregation.”
This reduces the segregation of chromatin’s structural elements, such as loops, domains, and compartments, disrupting the cell’s careful organization. This forms the basis for activating oncogenes, or genes that contribute to cancer development.
The researchers also found that the effects of WGD on chromatin organization are largely independent of chromosomal changes, suggesting that WGD and chromosomal instability are complementary mechanisms promoting cancer development.
In the future, highly multiplexed single-cell molecular profiles in combination with barcode technologies and new computational approaches could help determine the role of the disorganization of Chromatin’s 3D structure in transforming a cell into a cancer cell.
- Ruxandra A. Lambuta, et al. Whole genome duplication causes oncogenic loss of chromatin segregation. Nature. DOI: 10.1038/s41586-023-05794-2