Piecing together a genetic puzzle
A European team of scientists has discovered how cells accurately inherit information that is not contained in their genes. The research, presented in the journal Developmental Cell, was funded in part by the EPICENTROMERE ('Determining the epigenetic mechanism of centromere propagation') project, which has clinched a Marie Curie Action 'International Reintegration Grant' worth EUR 100 000 under the EU's Seventh Framework Programme (FP7). The results help piece together a puzzle on the biological processes of genes and cells, and in particular on cell division.
While the adult human body's 10 trillion cells are genetically identical, they develop into distinct types of cells including nerve cells, skin cells and muscle cells. This distinctive quality is triggered by the activation of some genes and the inhibition of others. Specialised cells have the capacity to keep a memory of their individual identity by remembering which genes need to be active or not, even when making copies of themselves.
Led by Lars Jansen from the Instituto Gulbenkian de Ciência (IGC) in Portugal, researchers say that while this type of memory is not written directly into the deoxyribonucleic acid (DNA), it is heritable. Meanwhile, non-genetic or 'epigenetic' instructions usually appear to be contained in proteins, and control both genes and the arrangement of chromosomes.
The team discovered how one of these epigenetic organising centres is passed on from mother to daughter cells. The findings could help scientists determine how a glitch in the cell division process can trigger cancer.
The researchers put the spotlight on the centromere, a protein structure on each chromosome that attaches it to the skeleton of the cell (cytoskeleton) during the division of the cell. This effectively guarantees that each daughter cell gets one set of new chromosomes. The scientists emphasise the importance of correctly functioning centromeres..When the process is not perfect, cells can receive an incorrect number of genes, which then leads to the emergence of tumour cells.
'When cells divide, they make exactly two copies of all genes, to be passed on to exactly two cells,' explains lead author Mariana Silva, a doctoral student from the Jansen lab. '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? This question is still mystifying scientists. We focused our efforts on the centromere because the key protein responsible for its epigenetic behaviour is known.'
This protein, known to scientists as CENP-A, keeps a 'molecular memory' of the centromere, ensuring its inheritance. Past studies carried out by Dr Jansen and colleagues found that while cells duplicate their DNA before mitosis, duplication of the centromere, led by the CENP-A protein, takes place only after mitosis. But no one knew what the triggering factor of the duplication is or how accuracy is guaranteed ... until now.
In this latest study, the researchers point out how the same machinery controlling the recognised process of DNA duplication is also controlling CENP-A duplication. This machinery acts like a molecular clock, driving the various steps of the cell cycle forward, one after the other.
Commenting on the results, Dr 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, how genomes are organised, and the wide spectrum of diseases that result from errors in these mechanisms.'
Experts from the United Kingdom and the United States contributed to this study.