Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 99, Issue -, Pages 16485-16490Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.182427299
Keywords
histone methylation; chromatin; RIP; epigenetics; DNA methyltransferase
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Funding
- NIGMS NIH HHS [GM35690, R01 GM035690, R37 GM035690] Funding Source: Medline
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One can imagine a variety of mechanisms that should result in self-perpetuating biological states. It is generally assumed that cytosine methylation is propagated in eukaryotes by enzymes that specifically methylate hemimethylated symmetrical sites (e.g., (5)'CpG/GpC(5)' or (5)' CpNpG/GpNpC(5)'). Although there is wide support for this model, we and others have found examples of methylation that must be propagated by a different mechanism. Most methylated regions of the Neurospora genome that have been examined are products of repeat-induced point mutation, a premeiotic genome defense system that litters duplicated sequences with C-G to T-A mutations and typically leaves them methylated at remaining cytosines. In general, such relics of repeat-induced point mutation are capable of triggering methylation de novo. Nevertheless, some reflect a mechanism that can propagate heterogeneous methylation at nonsymmetrical sites. We propose that de novo and maintenance methylation are manifestations of a single mechanism in Neurospora, catalyzed by the DIM-2 DNA methyltransferase. The action of DIM-2 is controlled by the DIM-5 histone H3 Lys-9 methyltransferase, which in turn is influenced by other modifications of histone H3. DNA methylation indirectly recruits histone deacetylases, providing the framework of a self-reinforcing system that could result in propagation of DNA methylation and the associated silenced chromatin state.
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