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J. Biol. Chem., Vol. 275, Issue 26, 19603-19608, June 30, 2000

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Methylation-dependent Silencing of the Testis-specific Pdha-2 Basal Promoter Occurs through Selective Targeting of an Activating Transcription Factor/cAMP-responsive Element-binding Site^*

Rocco C. Iannello^§, Jodee A. Gould, Julia C. Young, Antonietta Giudice, Robert Medcalf^¶, and Ismail Kola

From the  Centre for Functional Genomics and Human Disease, Monash Institute of Reproduction and Development, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia and the ^¶ Department of Medicine, Box Hill Hospital, Nelson Road, Box Hill, Victoria 3128, Australia

In this study, we demonstrate that methylation-dependent repression of the Pdha-2 core promoter is mediated regionally through a consensus activating transcription factor/cAMP-responsive element-binding site located between nucleotides 54 and 62 upstream of the major transcriptional start site. Targeting of the CpG dinucleotide within this cis-element significantly disrupts the ability of this basal promoter to activate gene expression in vitro and completely abolishes promoter activity in vivo. DNase I footprinting experiments indicated that availability of the nuclear factor(s) binding this element is limiting in sexually immature mouse testis, and as such, these factors may play an important role in the coordinate activation of early spermatogenic gene expression. Interestingly, CpG dinucleotides associated with the hypersensitive region flanking the activating transcription factor/cAMP-responsive element-binding site appear to confer some conformational structure on the promoter since mutations at these specific CpG dinucleotides result in elevated basal levels of transcription. This raises the possibility of a potential bifunctional role for CpG dinucleotides in either methylation-dependent or -independent processes. Our data support the notion that hypomethylation and transcription factor recruitment are necessary events that precede gene activation at the early stages of spermatogenesis.

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