Nature Structural & Molecular Biology11, 1068 - 1075 (2004)
Published online: 3 October 2004; | doi:10.1038/nsmb840
Intragenic DNA methylation alters chromatin structure and elongation efficiency in mammalian cells
Matthew C Lorincz1, David R Dickerson1, Mike Schmitt2
& Mark Groudine1, 2
1
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
2
Department of Radiation Oncology, University of Washington School of Medicine, Seattle, Washington 98195, USA.
Correspondence should be addressed to Matthew C Lorincz mlorincz@fhcrc.org
Transcriptional silencing in mammals is often associated with promoter methylation. However, a considerable number of genomic methylated CpGs exist in transposable elements, which are frequently found in intronic regions. To determine whether intragenic methylation influences transcription efficiency, we used the Cre/loxP-based system, RMCE, to introduce a transgene, methylated exclusively in a region downstream of the promoter, into a specific genomic site. This methylation pattern was maintained in vivo, and yielded a clear decrease in transgene expression relative to an unmethylated control. Notably, RNA polymerase II (Pol II) was depleted exclusively in the methylated region, as was histone H3 di- and trimethylated on Lys4 and acetylated on Lys9 and Lys14. As the methylated region adopts a closed chromatin structure in vivo, we propose that dense intragenic DNA methylation in mammalian cells initiates formation of a chromatin structure that reduces the efficiency of Pol II elongation.
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