Freiburg, Germany. A specific protein triggers the formation of centromeres, the specialized genome regions that are the primary constriction in X-shaped chromosomes.

The new discovery, reported in the journal Science, may stimulate further development of artificial human chromosomes, which could be used for research and practical gene therapies in medicine.


The cell skeleton, which distributes the chromosomes to the two daughter cells during cell division, attaches to the centromeres, which provide a platform for the development of a protein complex known as the kinetochore, enabling the chromosomes to move to the opposite poles of the cell. Scientists from the Max Planck Institute of Immunobiology and Epigenetics in Freiburg have succeeded in demonstrating that the position, function and inheritance of the centromere are determined by the histone CenH3, a DNA packaging protein.


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Epigenetic Inheritance of Centromeres

The lead image to this article is that of a stretched chromatin fibre; the CenH3 with a DNA binding domain (green) targets a specific DNA sequence (red). This leads to recruitment and spreading of endogenous CenH3 (blue) into neighbouring regions, an important property that allows the self-propagation of the epigenetic centromere mark.

This diagram depicts the epigenetic inheritance of centromeres, as it occurs in higher organisms with a cell nucleus. During cell division, the histone CenH3 ensures that new protein is integrated into the two DNA strands. The position of the centromere can thus be passed on from one generation to the next.

All images courtesy of the Max Planck Institute of Immunobiology and Epigenetics.In most organisms the position of the centromere is not determined by the DNA building blocks, — the DNA sequence — but epigenetically. The only exception to this rule is the unicellular fungus baker's yeast, in which a specific DNA sequence encodes the position of the centromere. A particularly promising candidate for this kind of epigenetic centromere marking is a variant form of the H3 histone known as CenH3.



Patrick Heun, PhD, is a Principal Investigator, Department of Cellular & Molecular Immunology, at the Max Planck Institute of Immunobiology and Epigenetics (Freiburg, Germany).Histone proteins bind DNA largely independently of the underlying sequence and help package the long thread-like DNA molecule. CenH3 arises exclusively in DNA regions at the centromere in various organisms. Patrick Heun's research group at Max Planck and colleagues from the Helmholtz Research Center in Munich have now discovered that CenH3 alone is sufficient to trigger the formation of the centromere.

The researchers equipped the CenH3 histone with an artificially attached DNA binding domain so that the protein could bind to a DNA region where a centromere does not normally form. However, a functioning kinetochore arose there which interacted with the cell skeleton during cell division. Using this approach, the researchers succeeded in distributing artificial minichromosomes between the two daughter cells during cell division.

The protein is able to recruit additional CenH3 proteins independently. "This ensures that sufficient CenH3 is available at the centromere after each cell division. Otherwise, the available CenH3 proteins would be reduced by half after each cell division. In this way, the centromere position can be passed on from generation to generation," says Heun.

The step from a DNA-identified centromere in baker's yeast, in which the position is fixed, to a protein-defined centromere position which is easier to change, may also play a role in evolution. Despite being up to several million DNA building blocks in size, centromeres can jump to other positions without causing the DNA to move.

Consequently, in rare cases, a new centromere can arise as it has already occurred in a closely-related ape species. Therefore neo-centromeres might contribute to the emergence of new species.

The insights into the central role of CenH3 for centromere identity could also prove important for medicine. Scientists would like to develop artificial human chromosomes as an alternative to gene therapy using viruses. "Like their natural counterparts, these require a centromere for cell division. Up to now it has not been possible to control the development of a centromere efficiently," says Heun.

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