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Methylation of CpG Dinucleotides Alters Binding and Silences Testis-Specific Transcription Directed by the Mouse Lactate Dehydrogenase C Promoter¹

^a Department of Biochemistry, Molecular Biology, and Cell Biology, Northwestern University, Evanston, Illinois 60208

ABSTRACT

The mouse lactate dehydrogenase c gene (mldhc) is transcribed only in cells of the germinal epithelium. Cloning and analysis of the mldhc promoter revealed that a 100-base pair fragment was able to drive testis-specific transcription in vitro and in transgenic mice. Several testis-specific genes are believed to be regulated at least in part through differential methylation of CpG dinucleotides. We investigated the possibility that transcriptional repression of the mldhc gene is mediated in somatic tissues by hypermethylation of CpG dinucleotides. The CpG dinucleotides within a fragment of the mldhc promoter containing a GC box and tandem activating transcription factor/cAMP-responsive element binding sites are hypermethylated in somatic tissues and hypomethylated in testis. Methylation of the activating transcription factor/cAMP-responsive elements altered the protein binding pattern observed in electrophoretic mobility shift assays using mouse liver but not testis nuclear extract. Furthermore, methylation of an extended mldhc promoter fragment driving lac Z silenced transcription from the promoter in a transient transfection assay. These data suggest that tissue-specific differential methylation plays a role in mldhc silencing in somatic tissues.

FOOTNOTES

First decision: 6 April 2001.

¹ This work was supported by NIH grants HD05863 (to E.G.) and 5T32HD07068 (to D.J.M.) and by Fogarty International Center Sub 521215/D43-TW00654 (to P.J.).

² Correspondence: Erwin Goldberg, Department of Biochemistry, Molecular Biology, and Cell Biology, Northwestern University, 2153 Sheridan Rd., Evanston, IL 60208. FAX: 847 467 1380; erv{at}northwestern.edu

³ Current address: University of California, San Francisco, CA 94143-0512.

⁴ Current address: Center for Reproductive Biology, School of Molecular Biosciences, Washington State University, Pullman, WA 99164-4660.

⁵ Current address: Emory University, Atlanta, GA 30322.

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