Researchers Stir Up Epigenetic Regulation

The Faculty of 1000 is a Web-based literature awareness tool published by BioMed Central. It provides a continuously updated insider's guide to the most important peer-reviewed papers within a range of research fields, based on the recommendations of a faculty of more than 1,400 leading researchers. Each issue, The Scientist will publish a list of the 10 top-rated papers from a specific subject area, as well as a short review of one or more of the listed papers. We will also publish a selection of comments on interesting recent papers from the Faculty of 1000's output. For more information, visit www.facultyof1000.com. First came DNA methylases; then, histone deacetylases. Chromatin specialists thought they understood the steps to explain epigenetic regulation of gene expression: DNA gets methylated, recruits histone deacetylases, and together these two systems button down chromatin and silence expression (See Hot Papers "The Complexity of Gene Silencing"). But two years ago, this simple picture began unraveling when histone methyltransferases were discovered. And now, in a paper from the Faculty of 1000's Top 10 Cell Biology papers for Jan. 16, Eric Selker of the University of Oregon's Institute for Molecular Biology stirs up the field once again by showing that histone methylation is in the driver's seat when it comes to orchestrating chromatin structure.1 Selker's work has provided a "very credible new insight into epigenetic silencing," says University of Virginia's Dave Allis, a leader in the field of histone modification. F1000 Top 10Cell Biology 1. P. Nash et al., "Multisite phosphorylation of a CDK inhibitor sets a threshold for the onset of DNA replication," Nature, 414:514-21, Nov. 29, 2001. 2. R.C. Robinson et al, "Crystal structure of Arp2/3 complex," Science, 294:1679-84, Nov. 23, 2001. 3. H.Tamaru, E.U. Selker, "A histone H3 methyltransferase controls DNA methylation in Neurospora crassa," Nature, 414:277-83, Nov. 15, 2001. 4. J. Rosenblatt et al., "An epithelial cell destined for apoptosis signals its neighbors to extrude it by an actin- and myosin-dependent mechanism," Current Biology, 1:1847-57, Nov. 27, 2001. 5. M. Groszer et al., "Negative Regulation of Neural Stem/Progenitor Cell Proliferation by the Pten Tumor Suppressor Gene in Vivo," Science, 294:2186-9, Dec. 7, 2001. 6. I.-E. Gallouzi, J.A. Steitz, "Delineation of mRNA Export Pathways by the use of Cell-Permeable Peptides," Science 294:1895-901, Nov. 30, 2001. 7. M. Lagos-Quintana et al., "Identification of Novel Genes Coding for Small Expressed RNAs," Science, 294:853-8, Oct. 26, 2001. 8. D.H. Mauch et al., "CNS Synaptogenesis Promoted by Glia-Derived Cholesterol," Science, 294:1354-7, Nov. 9, 2001. 9. R. Voulhoux et al., "Involvement of the twin-arginine translocation system in protein secretion via the type II pathway," European Molecular Biology Organization Journal, 20:6735-41, December, 2001. 10. L. Trusolino et al., "A Signaling Adapter Function for a6b4 Integrin in the Control of HGF-Dependent Invasive Growth," Cell, 107:643-54, November, 2001. Working with Neurospora, the simplest eukaryote which methylates its DNA, Selker and colleagues isolated a series of mutants deficient in methylation (dim mutants). The first of these to be characterized, dim-2, turned out predictably to code for a DNA methyltransferase. But the most recent to be identified, dim-5, the subject of Selker's Nature paper, surprisingly codes for a histone methyltransferase. This finding was foreshadowed by Selker's earlier work. He found that by inhibiting histone deacetylases, he also could prevent DNA methylation.2 This result planted the first seed that histone modification might be a prerequisite for DNA modification, but it went against the prevailing view that had DNA methylation as the defining step. Selker and his postdoc Hisashi Tamaru first tracked down dim-5 by using conventional genetic analysis to map this gene to a small segment of linkage group IV, and then used molecular genetics to pull that region out of the Neurospora genome. Selker says they found a gene homologous to several chromatin-associated proteins involved with gene silencing, the Clr4 gene of S. pombe and the Su3-9 gene of Drosophila. To see if this was the correct gene, they investigated whether Neurospora fragments that are homologous to Clr4 and Su3-9 would restore function to dim-5 mutants in a Neurospora transformation system. They did. Sequence analysis of the dim-5 gene provided a hint to the protein's function. Selker and Tamaru found a point mutation in a region of the DIM-5 protein called the SET domain. This finding was informative, as SET domains are found in histone methyltransferases. To see if this was in fact what DIM-5 did, Selker says they devised a scheme to test for a role in histone methylation in vivo. They created Neurospora mutants with an alteration on the histone H3 site, which is modified by histone methylases, lysine-9. Neurospora stained with this residue, replaced with either leucine or arginine, behaved like dim-5 mutants and were defective in DNA methylation. The story doesn't end here. Selker explains, "Assuming that histone methyltransferase is calling the shots, telling [DNA methyltransferases] where to methylate, the next question is 'What is controlling it?'" Laura DeFrancesco (defrancesco1@earthlink.net) is a freelance writer in Pasadena, Calif. References 1. H.Tamaru, E.U. Selker, "A histone H3 methyltransferase controls DNA methylation in Neurospora crassa," Nature, 414:277-83, Nov. 15, 2001. 2. E.U. Selker, "Trichostatin A causes selective loss of DNA methylation in Neurospora," Proceedings of the National Academy of Sciences, 95: 9430-5, Aug. 4, 1998.

Researchers Stir Up Epigenetic Regulation

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