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Molecular and Cellular Biology, January 2008, p. 836-848, Vol. 28, No. 2
0270-7306/08/$08.00+0     doi:10.1128/MCB.01088-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

A Mouse Gene That Coordinates Epigenetic Controls and Transcriptional Interference To Achieve Tissue-Specific Expression ^,

Alexandra C. Racanelli,^1, Fiona B. Turner,^1, Lin-Ying Xie,¹ Shirley M. Taylor,² and Richard G. Moran^1*

Departments of Pharmacology and Toxicology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298,¹ Department of Microbiology and Immunology and Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298²

Received 19 June 2007/ Returned for modification 7 August 2007/ Accepted 12 October 2007

The mouse fpgs gene uses two distantly placed promoters to produce functionally distinct isozymes in a tissue-specific pattern. We queried how the P1 and P2 promoters were differentially controlled. DNA methylation of the CpG-sparse P1 promoter occurred only in tissues not initiating transcription at this site. The P2 promoter, which was embedded in a CpG island, appeared open to transcription in all tissues by several criteria, including lack of DNA methylation, yet was used only in dividing tissues. The patterns of histone modifications over the two promoters were very different: over P1, histone activation marks (acetylated histones H3 and H4 and H3 trimethylated at K4) reflected transcriptional activity and apparently reinforced the effects of hypomethylated CpGs; over P2, these marks were present in tissues whether P2 was active, inactive, or engaged in assembly of futile initiation complexes. Since P1 transcriptional activity coexisted with silencing of P2, we sought the mechanism of this transcriptional interference. We found RNA polymerase II, phosphorylated in a pattern consistent with transcriptional elongation, and only minimal levels of initiation factors over P2 in liver. We concluded that mouse fpgs uses DNA methylation to control tissue-specific expression from a CpG-sparse promoter, which is dominant over a downstream promoter masked by promoter occlusion.

Published ahead of print on 12 November 2007.

Supplemental material for this article may be found at http://mcb.asm.org/.

A.C.R. and F.B.T. contributed equally to this work.