The A, B, Gs of silencing
- Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA
This extract was created in the absence of an abstract.
Transcriptional silencing of mammalian genes is mediated by at least two modes of methylation: (1) cytosine methylation of DNA, and (2) methylation of the histones tails—both of which play an important role in transcriptional silencing from chromosomal DNA. Although there is some evidence that these pathways are interdependent, experimentally, they have largely been treated as two distinct processes. In this issue of Genes & Development, Smallwood et al. (2007) have taken a pioneering step toward defining the molecular mechanism by which these two types of methylations can cooperate to silence a euchromatic gene, and demonstrate that the DNA methyltransferase 1 (DNMT1) cytosine methyltransferase physically and functionally interacts with three Heterochromatin Protein 1 (HP1) family members (α, β, and γ) to implement gene silencing.
DNA methylation is required for normal development in mammals. It is brought about by the de novo methyltransferases DNMT3a and DNMT3b and is propagated by the maintenance methyltransferase DNMT1 (for review, see Goll and Bestor 2005). DNA methylation is associated with silencing repetitive elements in the genome, X-chromosome inactivation in female mammals, and silencing of individual genes during development (for review, see Li and Bird 2007). Furthermore, DNA methylation is misregulated in cancer cells such that tumor suppressor genes are silenced to favor the growth of the tumor while repetitive regions of the genome are desilenced, which can contribute to genomic instability (for review, see Baylin and Jones 2007). However, the exact molecular mechanism of DNA methylation in transcriptional regulation and during the pathogenesis of cancer remains unclear.
The core histone proteins are wrapped by 147 base pairs of DNA forming the intact nucleosome. The histone N termini, or tails, extend away from the core of the nucleosome and are available for interactions with the DNA, histone-modifying enzymes, and other proteins, which alter the nucleosome structure …
