Chromosomes change their address in response to their environment
08 May 2018
By Dr. Kundan Sengupta, Intermediate Fellow
Indian Institute of Science Education and Research (IISER), Pune
The human body has many different types of cells which can be distinguished from one another by their shape and stiffness. The brain is a very soft tissue; while kidney, liver and intestine are of intermediate stiffness and bones are very stiff. The stiffness of the tissue is a combined property of cells and their interaction with the environment. Most remarkably, changes in the stiffness of the environment relays information into the nucleus directing gene expression to cater to the functions of that tissue.
The nucleus houses DNA as chromosomes, that are organized as specific territories in the 3-dimensional space of the nucleus. Chromosomes find their address inside the nucleus reproducibly across cell division cycles. Chromosomes containing more genes (gene-rich) are located in the nuclear interior, while chromosomes with less genes (gene-poor) are closer to the edge of the nucleus. Does the stiffness of the tissue affect the organization of chromosomes in the nucleus and does this in turn affect gene expression?
Figure: Images of cells with chromosomes labelled in red and green. Each chromosome assumes a unique location or territory in the nucleus.
In the lab, cells are typically grown on stiff plastic dishes or glass coverslips. To assess the impact of substrate stiffness on the genome, we exposed colon cancer cells to two extremes of stiffness - soft gels and stiffer glass coverslips. Interestingly, we found that gene-poor chromosomes moved from their otherwise peripheral position into the nuclear interior simply by exposing cells to softer matrices for ~90 minutes. Chromosome locations responded very quickly to changes in stiffness of the environment, as they returned to their original locales in ~90 min, in cells transferred back to glass. These results highlight the remarkable plasticity of our genomes and its rapid response to changes in the mechanical properties of its external milieu. Further, we discovered that a protein - Emerin, which resides in the inner nuclear membrane undergoes a modification (phosphorylation) in cells exposed to soft gels and serves as a key relay signal to activate changes in chromosome locations.
The relative location of chromosome territories determines the type and quantity of gene expression in the form of RNA – a chemical cousin of DNA. Our studies show that RNA levels are directly altered by the interaction of a cell with its environment, which is cell type specific. Our studies require further investigation of tissue type and cell type specific location and expression of chromosomes in response to changes in the stiffness of their external environment. This approach will provide tantalizing clues of how aberrant signals perceived by cells within a tissue are likely to convert seemingly normal cells to cancer – a devastating disease that poses major challenges to all of mankind!
Emerin modulates spatial organization of chromosome territories in cells on softer matrices. Pradhan R, Ranade D and Sengupta K. Nucleic Acids Research. April 2018
Banner image credit: Dr. Kundan Sengupta. Description: Cells exposed to softer gels or matrices begin to spread as shown by cells producing extensions or cable like projections (green). This shows how changes in the properties i.e stiffness of the external environment affects cell shapes, which in turn affects locations of chromosomes in the nucleus.