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Keep chromatin locked? Ask for the right combination!

Diagram showing a mitotic chromosome, the centromere, chromatin and the role of the studied H3K64me3 trimethylation in formation and maintenance of the pericentromeric heterochromatin.

Dissecting the role of H3K64me3 in mouse pericentromeric heterochromatin.

Lange UC, Siebert S, Wossidlo M, Weiss T, Ziegler-Birling C, Walter J, Torres-Padilla ME, Daujat S, Schneider R.

Nat Commun 2013

Aug. 1, 2013


Robert Schneider’s team at IGBMC has demonstrated the importance of a histone modification (H3K64me3) in maintaining constitutive heterochromatin integrity. They provide new insights into the molecular signalling cascade that stabilizes the pericentromeric region of chromosomes, crucial in the prevention of genomic instability. Their results are published on first August in the journal Nature Communications.

Shaping DNA

A cell observed under a microscope shows variation in the shape of chromosomes according to the cell cycle stage. This variation, due to changes in the compaction level of the genome, is the result of proteins, the histones, which by interacting with DNA form the chromatin. There are two types of chromatin: euchromatin and heterochromatin. Condensation / decondensation of chromatin is essential in the expression of genetic information. The degree of condensation is low in euchromatin, referred to as "open", and accessible to the transcription machinery. It is high in heterochromatin, described as "closed" and usually "inaccessible" to the same machinery. This compaction is regulated by modifications brought on histones, such as, for example, methylations.

In the present case, researchers were interested in the heterochromatin near the centromere region of the chromosome. The centromere is the contact point between the four arms of the mitotic chromosome (see figure). In their previous study, they had, in fact, noted in mouse an important trimethylation (addition of three methyl groups) on a specific amino acid, lysine 64, in this genomic region (more precisely on histone H3). This change, called H3K64me3, is dynamic during early development of mouse, disappearing at certain stages. In this new study, they wanted to know the function of this chemical fingerprint in the formation and maintenance of this so-called pericentromeric heterochromatin.


Using the backdoor

Actors of the molecular cascade leading to the establishment of the pericentromeric chromatin are known (Figure). In contrast, the enzyme responsible for lysine 64 trimethylation has not yet been identified. To understand the role of H3K64me3, researchers had to take a circuitous route. They used mouse cells in which, in turn, the protagonists of this cascade were rendered inactive and studied the effect of this inactivation on H3K64me3.

Researchers were surprised to find that these inactivations had no effect, proving that H3K64me3 is independent of the classical process of establishment of the pericentromeric heterochromatin. If it occurs in a parallel signalling pathway, H3K64me3 remains however directly dependent on another methylation H3K9me3 (lysine 9 trimethylation), located upstream. In contrast and more importantly, H3K64me3 can exercise a positive influence on the key players in the shaping of pericentromeric heterochromatin. This methylation could improve stability of this type of chromatin in order to preserve its integrity and help prevent the development of certain diseases such as cancer. In fact, anomalies involving epigenetic alterations including of heterochromatin players have been found in many types of cancer.

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