Centromere memory encoded in the One Generation Deep epigenome

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About one-third to two-thirds along the stem of a chromosome is a tight site called a centromere. When a chromosome replicates, the old and the new pair (called chromatids) are held together at that centromere. During cell division, centromeres bind to microtubules which pull old and new pairs to opposite ends of the dividing cell, ensuring that each daughter cell receives a complete set of the parent’s genome. Defects in the centromeres lead to abnormal distribution of DNA into daughter cells, which in turn can lead to cell death or cancer.

In a study on the transparent microscopic worm, Caenorhabiditis elegans, scientists have found that the transmission of the correct location of centromeres from parent to offspring is mediated not by genes, but by epigenetic memory.

The study carried out by two teams from the University of Geneva (UNIGE) and published in the PLOS Biology article “The transgenerational inheritance of the centromere identity requires the N-terminal CENP-A tail in the C. elegans maternal germ line»Was financially supported by the Swiss National Science Foundation and the Republic and Canton of Geneva.

From worms to humans, all living organisms inherit physical and behavioral traits from their parents. Most of these biological traits are inherited through DNA, but there are exceptions to this rule. Certain characteristics can be passed from one generation to the next, independent of genes by epigenetic means.

Florian Steiner, PhD, professor in the molecular biology department of UNIGE is the main author of this study.

Florian Steiner, PhD, professor in the molecular biology department of UNIGE and principal author of this study, declares: “The transgenerational transfer of epigenetic information not only exists, but can be understood molecularly (which is not yet also clear in humans). This epigenetic transfer from one generation to the next may differ from cell-to-cell inheritance. It is therefore important to study these processes in organisms in addition to cultured cells.

Reinier Prosée, PhD, researcher in the molecular biology department of UNIGE and first author of the study explains: “The study of these processes is greatly facilitated in C. elegans, because this little worm is transparent and allows direct observation of cell divisions and the fate of chromosomes from one generation to the next.

Reinier Prosée, PhD, researcher in the molecular biology department of UNIGE is the first author of the study.

The location of the centromere on the chromosome is defined by a histone protein called Centromere Protein A (CENP-A) which is the research object of the groups of Steiner and Monica Gotta, PhD, professor at the Faculty of Medicine of the ‘UNIGE. Together, the Steiner and Gotta teams discovered that CENP-A finds its location on the chromosome to define the centromere using a particular region of DNA that serves as a guide. The researchers then mutated this region of DNA that guides CENP-A.

“The prediction was that this mutant would not be viable, because the position of the centromere could not be defined in the absence of the guide part of the protein. We expected that this would lead to an incorrect distribution of chromosomes, ”says Steiner.

“However,” says Prosée, “we have found that even in the absence of this ‘guide’ region, the truncated protein positions correctly and is functional. The worms are therefore perfectly viable!

Once the centromeric sites have been defined in the mother, this information is transmitted to the next generation even in the absence of the DNA which codes for the “guide” region of the protein, the authors deduce. In contrast, the offspring of mutant worms cannot properly divide their cells and therefore do not survive because they did not inherit epigenetic information about the correct position of the centromeric sites from their mutant mother. This epigenetic memory lasts only one generation and is not passed on to the next.

“We have combined traditional worm genetics and fluorescence microscopy with more recently developed techniques, such as the auxin-inducible degron (AID) system to degrade proteins in a specific tissue at a specific point of development. This was important to distinguish the roles of CENP-A and KNL-2 [a protein that binds to CENP-A] in the germ line of those under development, ”says Steiner. “We had to generate several precise deletions in the endogenous CENP-A gene to remove specific parts of the protein and add tags to be able to detect these mutant proteins. This would not have been possible with the techniques that existed before the development of the CRISPR / Cas9 genome editing technique. “

In their next experiments, Steiner’s team will try to explain the epigenetic mechanism by which this memory is made and persists through the stages of development.


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