Oeiras, Portugal. Scientists continue their progress in understanding how epigenetic instructions are passed on from mother to daughter cells with extremely high — but not absolute — fidelity, most recently providing insights into a key cell division process.

A science team has worked out how one of these epigenetic organizing centers is passed on, elucidating an important biological process, while identifying what can happen when it goes wrong.


All 10 trillion cells in the adult human body are genetically identical, but develop into distinct cell types, such as neurons, muscle cells, or skin cells, by activating some genes while inhibiting others. Each specialized cell maintains a memory of their individual identity by remembering which genes should be kept on or off, even when making copies of themselves. This type of memory is not written directly into the DNA, yet it is heritable. Instead, such non-genetic (or epigenetic) instructions often appear to be contained in proteins and control not only genes but also how chromosomes are organized.

Cell Cycle Seen in Human Cancer Cells

The lead image (at the top of this article) shows the cell cycle seen in human cancer cells.

The cell on the left, the middle one and the cell on the right are at different sages of mitosis (cell division): their duplicated chromosomes (in blue) align along the midline (cell on the left), and then are pulled towards the poles of the cell (middle and right-hand cell), by protein cables (in green).

The top cell has finished mitosis and is entering gap phase G1, when centromeres are duplicated, as seen by newly made CENP-A (in red).

Image courtesy of Mariana Silva and Lars Jansen, Instituto Gulbenkian de Ciência (IGC).Lars Jansen and his team at the Instituto Gulbenkian de Ciência (IGC) focused on the centromere, a unique protein structure on each chromosome that attaches it to the cell's skeleton (cytoskeleton) during cell division and thus ensures that each daughter cell receives exactly one set of freshly made chromosomes. A properly functioning centromere is critical, as loss in accuracy of this process results in cells with the wrong number of genes, a hallmark of tumor cells. Their findings appear in the journal Developmental Cell.

When cells divide they make exactly two copies of all genes, to be passed on to exactly two cells. A similar feat has to be pulled off for non-genetic information. But how does the cell copy a protein structure? And, how does it ensure just the right number of copies are made? Mariana Silva, a PhD student in the lab, and first author of the study, says the team focused their efforts on the centromere because the key protein responsible for its epigenetic behavior is known.

This protein, called CENP-A, keeps a molecular memory of the centromere, ensuring its inheritance. Previous studies, by Lars and other research groups, had shown that, while cells duplicate their DNA before mitosis, duplication of the centromere, led by the CENP-A protein, takes place only after mitosis (during a 'gap' phase called G1). What triggers its duplication and how accuracy is ensured remained unknown.



Epigenetics Mechanism Laboratory

Pictured are group leader Lars Jansen (first on the left) and Ph.D. student Mariana Silva (fourth from left).

Image courtesy of the Instituto Gulbenkian de Ciência (IGC).Jansen and his team show that the same machinery that controls the well-known process of DNA duplication also controls CENP-A duplication. This machinery, that includes the so-called cyclin-dependent kinases (Cdks) acts like a molecular clock driving the different steps of the cell cycle forward, one after the other. When Cdks are highly active (just before mitosis) DNA duplicates while duplication of CENP-A is inhibited.

Conversely, when they are inactive (after mitosis), CENP-A is duplicated but at that point DNA duplication is inhibited. In other words, when DNA duplicates at midnight, Cdks make sure that the centromere is copied only at noon.

The IGC researchers came to this elegant model by painstainkingly inhibiting Cdk activity in human and chicken cells at set times. When doing so, they could fool the cells into making new centromeres even while the cells were in the middle of duplicating their DNA. "It´s like a cell with a jetlag", says Lars Jansen.

Jansen says "What we've uncovered is a very simple, neat mechanism whereby the cell couples DNA duplication, cell division and centromere assembly. By using the same machinery (Cdks) for all these steps but in opposite ways, the cell makes sure that the right number of copies of both genes and centromeres are made by allowing each the appropriate time.

Keeping these critical processes separate in time might be important to avoid errors in either one. "Understanding these general principles of epigenetic inheritance are fundamental to our understanding of how genes are regulated", Jansen says, including "how genomes are organised, and the wide spectrum of diseases that result from errors in these mechanisms".

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