Methylation of the Cyclin A1 Promoter Correlates with Gene Silencing in Somatic Cell Lines, while Tissue-Specific Expression of Cyclin A1 Is Methylation Independent

doi:10.1128/MCB.20.9.3316-3329.2000

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Molecular and Cellular Biology, May 2000, p. 3316-3329, Vol. 20, No. 9
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Methylation of the Cyclin A1 Promoter Correlates with Gene Silencing in Somatic Cell Lines, while Tissue-Specific Expression of Cyclin A1 Is Methylation Independent

Carsten Müller,¹^,²^,^* Carol Readhead,³ Sven Diederichs,² Gregory Idos,¹ Rong Yang,¹ Nicola Tidow,¹ Hubert Serve,² Wolfgang E. Berdel,² and H. Phillip Koeffler¹

Division of Hematology/Oncology, Cedars-Sinai Research Institute/UCLA School of Medicine, Los Angeles, California 90048¹; Department of Medicine, Hematology/Oncology, University of Münster, Münster, Germany²; and Division of Biology, California Institute of Technology, Pasadena, California 91125³

Received 29 June 1999/Returned for modification 25 August 1999/Accepted 26 January 2000

Gene expression in mammalian organisms is regulated at multiple levels, including DNA accessibility for transcription factorsand chromatin structure. Methylation of CpG dinucleotides is thoughtto be involved in imprinting and in the pathogenesis of cancer.However, the relevance of methylation for directing tissue-specificgene expression is highly controversial. The cyclin A1 gene isexpressed in very few tissues, with high levels restricted tospermatogenesis and leukemic blasts. Here, we show that methylationof the CpG island of the human cyclin A1 promoter was correlatedwith nonexpression in cell lines, and the methyl-CpG binding proteinMeCP2 suppressed transcription from the methylated cyclin A1 promoter.Repression could be relieved by trichostatin A. Silencing of acyclin A1 promoter-enhanced green fluorescent protein (EGFP) transgenein stable transfected MG63 osteosarcoma cells was also closelyassociated with de novo promoter methylation. Cyclin A1 couldbe strongly induced in nonexpressing cell lines by trichostatinA but not by 5-aza-cytidine. The cyclin A1 promoter-EGFP constructdirected tissue-specific expression in male germ cells of transgenicmice. Expression in the testes of these mice was independent ofpromoter methylation, and even strong promoter methylation didnot suppress promoter activity. MeCP2 expression was notably absentin EGFP-expressing cells. Transcription from the transgenic cyclinA1 promoter was repressed in most organs outside the testis, evenwhen the promoter was not methylated. These data show the associationof methylation with silencing of the cyclin A1 gene in cancercell lines. However, appropriate tissue-specific repression ofthe cyclin A1 promoter occurs independently of CpGmethylation.

^* Corresponding author. Mailing address: Department of Medicine, Hematology/Oncology, ICP-Laboratory, University of Münster,Domagkstr. 3, 48129 Münster, Germany. Phone: 49-251-835-6229.Fax: 49-251-835-2673. E-mail: muellerc{at}uni-muenster.de.

Molecular and Cellular Biology, May 2000, p. 3316-3329, Vol. 20, No. 9
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

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