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

Abstract

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.

Gene regulation by the act of long non-coding RNA transcription

“…It has been suggested that silencing of an alternative promoter of the mouse fpgs pc gene is an example of transcription inducing silencing without introducing chromatin changes [82], but this system has not been subject to a similar genetic analysis and alternative explanations remain possible. How RNAPII from an interfering promoter is able to suppress functional transcription of the overlapped promoter remains to be determined, but stalling of the interfering RNAPII elongating over the sensitive promoter has been suggested to block access of essential TFs [30,83].…”

Evolution, biogenesis and function of promoter-associated RNAs

“…Indeed, in eukaryotes from yeast to mouse, transcription through promoter regions is known to disrupt transcription start sites and suppress gene expression (reviewed in refs. [27][28][29]. In these cases the production of the small RNA is functionally important, but the small RNA itself may not be.…”

XIII International Charles Heidelberger Symposium and 50 Years of Fluoropyrimidines in Cancer Therapy Held on September 6 to 8, 2007 at New York University Cancer Institute, Smilow Conference Center

“…Richard Moran studied the epigenetic control of tissue-specific expression for FPGS. He examined the contrast between the promoters in liver and kidney, and the promoters in proliferating tissues and tumor that utilized IRES and are unmethylated (56). …”