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Molecular mechanisms of gene silencing mediated by DNA methylation. | LitMetric

Molecular mechanisms of gene silencing mediated by DNA methylation.

Mol Cell Biol

Dipartimento di Biologia Strutturale e Funzionale, Università degli Studi dell'Insubria, 21052 Busto Arsizio (Va), Italy.

Published: May 2002

AI Article Synopsis

  • DNA methylation and chromatin modifications work together to repress gene transcription without needing to modify the promoter itself.
  • Experiments using microinjections into Xenopus oocytes showed that a certain number of methylated cytosines are necessary to create a stable chromatin structure that can inhibit a nearby promoter.
  • The study found that while histone deacetylation contributes to gene repression, it mainly occurs when methylation levels are low; also, the interaction between transactivators and methyl-binding proteins plays a key role in regulating gene expression.

Article Abstract

DNA methylation and chromatin modification operate along a common pathway to repress transcription; accordingly, several experiments demonstrate that the effects of DNA methylation can spread in cis and do not require promoter modification. In order to investigate the molecular details of the inhibitory effect of methylation, we microinjected into Xenopus oocytes a series of constructs containing a human CpG-rich sequence which has been differentially methylated and cloned at different positions relative to a specific promoter. The parameters influencing the diffusion of gene silencing and the importance of histone deacetylation in the spreading effect were analyzed. We demonstrate that a few methylated cytosines can inhibit a flanking promoter but a threshold of modified sites is required to organize a stable, diffusible chromatin structure. Histone deacetylation is the main cause of gene repression only when methylation does not reach levels sufficient to establish this particular structure. Moreover, contrary to the common thought, promoter modification does not lead to the greater repressive effect; the existence of a competition between transactivators and methyl-binding proteins for the establishment of an open conformation justifies the results obtained.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC133775PMC
http://dx.doi.org/10.1128/MCB.22.9.3157-3173.2002DOI Listing

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