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New link between epigenetic memory and mitotic chromosome size

 13 November 2020   Research News

By Dr Sophie Arthur

Cell division is an essential process that all cells must be able to perform for growth and repair. Mitosis is one phase of cell division, and it results in two so-called daughter cells, each with the same number of chromosomes as the parent cell. A crucial step in this process is making sure that the correct amount of genetic material (DNA), in the form of chromosomes, is accurately split between these two daughter cells.

However, it is not just genetic information that is passed from parent to daughter cells. Epigenetic information is ‘inherited’ too. Every single cell that is in our bodies contains the same DNA, but yet there are thousands of different cell types. Each type of cell has different genes that are switched on or off, which defines the ‘identity’ of the cell. Epigenetic modifications are added to the DNA which provide extra instructions to the cell and influence which genes are active or not.

During mitosis, it is essential that this epigenetic information is transmitted correctly to the daughter cells so that the cell identity is maintained after cell division. If this information is not maintained accurately, then it could result in altered cell identity, genomic instability or even cell death.

The chromosomes go through extensive changes during mitosis including becoming more condensed and tightly packed together. Exactly how the chromosomes go through this reorganisation during mitosis and transmit the cell identity to the daughter cells is poorly understood.

Researchers from the Lymphocyte Development group at the MRC LMS published a study on 17 August in Nature Communications which identifies some of the factors that could play a role in the passing on of epigenetic information during mitosis in mouse embryonic stem cells.

Working with the Flow Cytometry facility at the LMS, the team developed a novel technique that allows them to purify chromosomes going through mitosis. Having this technique allowed the researchers to examine which proteins were still bound to the chromosomes during mitosis, and which were most likely to fall off.

Image of flow-sorted chromosome

Rather than doing this one protein at a time, the team paired up with the Proteomics facility at the Institute to identify all the bound and unbound proteins at once. Interestingly, the group found several proteins remain bound to mitotic chromosomes that were already known to play a role in keeping genes ‘silent’.

These proteins included so-called chromatin repressors that keep genes switched off; proteins that influence the organisation and packing of the chromosomes; and proteins associated with pluripotency, such as Esrrb, which is known to ‘bookmark’ chromosomes during mitosis. Mitotic bookmarking is known to describe the factors that are important for re-establishing the epigenetic memory in the daughter cells.

The team tagged the repressor proteins with a fluorescent label in live cells, and analysed what happened as the cells divided into two. The fluorescent proteins stayed bound to the chromosomes throughout the process of mitosis. To explore whether this was important, the group removed the repressors from the cells, as well as cleaved the proteins within cells that were actually bound to the chromosomes, to reveal what would happen.

In both the mouse embryonic stem cells that had the repressor proteins removed, and in the cells where condensin, a key chromosome structural protein, had been cleaved from the chromosome, the researchers found that the chromosomes were larger than normal because the chromosomes are less condensed. Importantly, when these repressor proteins were added back to the cells, then the chromosomes returned to a more compact shape.

This research therefore reveals that these proteins have a previously unrecognised role in keeping chromosomes compact as cells go through mitosis, and play a part in ensuring that the epigenetic memory of the cell is transferred. What’s more, this new tool for purifying mitotic chromosomes offer a way to study the impact of specific proteins on chromosome structure and function, especially in mammalian cells and pluripotent mouse embryonic stem cells which wouldn’t have been possible before.

 

‘Identifying proteins bound to native mitotic ESC chromosomes reveals chromatin repressors are important for compaction’ was published in Nature Communications on 17 August. Read the full article here.