The role of H3K9 in bringing order to the nucleus

August 31, 2012, Friedrich Miescher Institute for Biomedical Research
Each progressive state of modification on H3K9 provided a signal that triggered the transfer of the modified nucleosomes to the nuclear envelope.

(—Scientists from the Friedrich Miescher Institute for Biomedical Research have elucidated the histone modifications that lead to the sequestration of silent genes at the nuclear periphery. In a study published in the latest issue of Cell they show that at least two levels of histone H3 lysine 9 methylation trigger the anchoring of heterochromatin to the nuclear envelope.

The is a hotbed of activity, in which DNA and numerous species of RNA are implicated in gene expression, genome duplication and repair, as well as the regulation of these essential processes. The organization of DNA into chromatin, which entails the folding of long DNA fibers around bead-like units containing 8 , is the defining feature of the eukaryotic genome. Once organized into these nucleosomes, chromatin can be compacted into condensed chromosomal structures, or unfolded to allow enzymes to act on their DNA substrate. Chromatin-controlled access to the DNA fiber regulates essentially all functions of the genome in a .

Intriguingly, as differentiate to form a multicellular organism, regions of the genome become packaged into compact silent domains, called heterochromatin. The total amount of heterochromatin in the cell increases as pluripotent differentiate into restricted cell types. Different genes are repressed in different tissues. The silent domains also become spatially segregated from the transcriptionally active ones, being shifted to the periphery of the nucleus. This spatial segregation of active and inactive domains of the genome is conserved in . The Gasser laboratory at the Friedrich Miescher Institute for Biomedical Research studies the physiological implications of this spatial organization. They have now elucidated in the worm C. elegans how the sequestration of genes at the nuclear periphery is achieved.

Benjamin Towbin, during the course of his PhD studies in Susan Gasser's laboratory, found that an enzyme called SAM synthetase, which generates the universal donor for lysine methylation, S-adenosylmethionine (SAM), is critical for the proper spatial segregation of chromatin in the nucleus. When he interfered with SAM synthesis he observed a strong drop in histone methylation, activation of what should have been silent genes in a heterochromatic context, and loss of their sequestration at the nuclear edge.

Assuming that the methylation of specific lysines within histones might be the signal for heterochromatin sequestration, Towbin then went on to determine which of the many enzymes that transfer a from SAM to a histone substrate, were necessary for heterochromatin anchoring. He identified two histone methyltransferases (HMTs), which act sequentially to generate a trimethylated lysine 9 in histone H3: MET-2 is a homologue of the mammalian SET DB1 enzyme, and deposits the first and second methyl group on this specific residue, while a new HMT, SET-25, was able to deposit the third methyl group, generating H3K9me3. Each progressive stage of modification, the mono-, di- and tri-methylated forms of H3K9, provided a signal that triggered the transfer of the modified nucleosomes to the . Intriguingly, mono- and di-methylated nucleosomes were not transcriptionally silent, but were necessary for the tri-methylation mark, which then closed down expression and sealed the bond to the periphery.

Towbin and colleagues could further show that SET-25 co-localizes with peripheral heterochromatin bearing tri-methylated H3K9. SET-25 is thus sequestered at the nuclear periphery by the product of its own methylation reaction. "We believe that SET-25 accumulates at the nuclear periphery to promote heterochromatic repression of the genes that are brought there due to deposition of the mono- and di-methyl marks. This also ensures that is targeted by the SET-25 enzyme as the chromatin replicates, an event that would favor the propagation of both a repressed state and its spatial positioning," says Towbin.

Although the results were gained in the model organism C. elegans, mammalian homologues exist for the identified proteins and similar processes have been described in mammalian cells, albeit in less detail. "The analogies to mammalian silencing suggest that the principles identified here are relevant from worms to man," said Gasser.

Explore further: Histone modifications control accessibility of DNA

More information: Towbin BD, González-Aguilera C, Sack R, Gaidatzis D, Kalck V, Meister P, Askjaer P, Gasser SM (2012) Step-wise methylation of histone H3K9 positions chromosome arms at the nuclear periphery in C. elegans embryos. Cell 150:934-947

Related Stories

Histone modifications control accessibility of DNA

July 14, 2010

( -- n an advanced online publication in Nature Structural & Molecular Biology scientist from Dirk Schübeler's group from the Friedrich Miescher Institute for Biomedical Research provide a genome-wide view of ...

Regulating the nuclear architecture of the cell

December 10, 2006

An organelle called the nucleolus resides deep within the cell nucleus and performs one of the cell's most critical functions: it manufactures ribosomes, the molecular machines that convert the genetic information carried ...

Silence of the genes

July 22, 2011

A molecular mechanism by which gene silencing is regulated at the genome-wide level in plants has been uncovered by a research team led by Motoaki Seki of the RIKEN Plant Science Center, Yokohama, Japan. The researchers ...

Core tenets of the 'histone code' are universal

September 6, 2007

In one of biology’s most impressive engineering feats, specialized proteins called histones package some six-and-a-half feet of human DNA into a nucleus that averages just five microns in diameter.

Work with fungus uncovering keys to DNA methylation

December 15, 2008

Researchers in a University of Oregon lab have shed more light on the mechanism that regulates DNA methylation, a fundamental biological process in which a methyl group is attached to DNA, the genetic material in cells of ...

Recommended for you

New species of lemur found on Madagascar

January 15, 2018

A team of researchers with members from the State University of New York Polytechnic Institute, Omaha's Henry Doorly Zoo and Aquarium, Global Wildlife Conservation and the Madagascar Biodiversity Partnership has discovered ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.