DNA Methylation Has a Local Effect on Transcription and Histone Acetylation

Abstract

DNA methylation is commonly associated with gene silencing, and a link between histone deacetylation and DNA methylation has been established. However, the transcriptional impact of the position and length of methylated zones relative to the promoter and the coding region of a gene remains quite unclear. This study investigates the impact of regional methylation on transcription and the relationship between DNA methylation and histone acetylation. Using patch-methylated stable episomes in human cells, we establish the pivotal importance of the location of DNA methylation in the regulation of transcription. We further demonstrate that the size of the methylated patch is not a key determinant for transcriptional suppression. The impact of DNA methylation on transcription is greater when it is in the transcription unit, and it is primarily a local effect. However, methylation outside of the transcription unit may potentiate the effect of methylation within the transcription unit. Acetylated histones are associated with unmethylated DNA and are nearly absent from methylated DNA regions. This association appears to be local and does not propagate along the DNA.

We thank David VanDenBerg for providing technical assistance for the TaqMan assays and for providing the TaqMan probes and primers for the XRCC1 analysis. We also thank M. R. Lieber, Y. Ma, and K. Yu for critical reading of the manuscript.

This work was supported by NIH grants RO1 GM54781 and RO1 GM60237. R.A.I. was supported by the ARCS Foundation.