The Scientist
Volume 25 | Issue 3 | Page 28
Date: 2011-03-01
By Robert E. Kingston
The Mark of Faith
Testing a central tenet of epigenetic regulation
A fundamental problem in biology concerns how the genomic information present in fertilized eggs can give rise to the full spectrum of stably differentiated cell types required to form vertebrates and invertebrates. In the 1930s, C.H. Waddington’s largely observational mammalian embryology studies, which defined this problem, were central to establishing the field of epigenetics. It is now well known that there are master regulatory genes that must be kept on to specify a given cell lineage and off in the many other cell lineages that make up the body.
The problem of keeping these genes in the off state when required has received considerable attention, in large part due to the landmark genetic studies initiated by Pam and Ed Lewis in the 1940s that identified a set of genes required for this repression. This family of genes is called the Polycomb Group (PcG) because the visual phenotype of a heterozygous null allele in these genes is duplication on the second and third legs of the sex combs that wild-type male Drosophila flies have on their front legs. It turns out that PcG proteins repress key developmental master regulatory genes in organisms from plants to humans. The PcG is responsible for a diversity of important biological events, from why plants flower only in the spring (and not in a December warm spell) to how mammals form the correct body tissues in the correct locations.
Based on C.H. Waddington, The strategy of the genes, 1957; Antagain / Istockimages.com (mouse);
Lucy Reading-Ikkanda (landscapes)
Lucy Reading-Ikkanda (landscapes)
Polycomb and histone methylation
Study of the PcG has converged with another active area related to epigenetics, the study of covalent modification of histones. The four core histones wrap DNA around them to form a nucleosome, and every gene is bound by nucleosomes, usually at one nucleosome for every ~147 base pairs of DNA. A physical mark on histones is one possibility for how regulatory information might be transmitted from an already differentiated cell to a daughter cell. For example, a covalent mark specifying repression might be found on the histones that coat a specific gene in a liver cell, and these histones might retain the repressive covalent mark when new nucleosomes are formed after DNA replication. One of the key protein complexes formed by the PcG gene products, Polycomb repressive complex 2 (PRC2), methylates lysine 27 of histone H3 (H3K27). This mark is widely believed to be an important component of epigenetic mechanisms and is believed to function by creating a binding pocket for another PcG complex (PRC1) that effects repression.
Yet many who work on gene regulation are skeptical that methylation of lysine 27 confers epigenetic information—in this instance meaning information that is heritable and transmitted from mother to daughter cell to specify that a master regulatory gene be kept off. Significant issues with the model include whether the marked histones are faithfully replaced on the gene following replication, whether the energy created by a binding pocket constituted by a methyl group is sufficient to do the repressive job, and whether placement of the methyl mark can be accomplished with sufficient accuracy to effect defined regulation.
In comparison, gene-specific DNA binding proteins, known to play a role in epigenetic regulation, bind to their sites with energies considerably more formidable than can be created by a methyl mark on a histone. These proteins recognize specific DNA sequences that are lengthy enough to be unique within the genome, and one can easily imagine that the proteins will rebind accurately to those sequences following replication and cell division.
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The fact that a hypothesis makes sense does not eliminate the need to test it as rigorously as possible. Hopefully, mammalian technologies will advance so that point mutation of residues perceived to be epigenetic can in fact be performed, because the spectrum of mechanisms that govern these issues is not the same in flies and mammals. Until such definitive experiments are performed, skeptics will have free run, and the field will continue to spin its wheels.
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