DNA demethylation-dependent AR recruitment and GATA factors drive Rhox5 homeobox gene transcription in the epididymis

Anjana Bhardwaj, Hye Won Song, Marcy Beildeck, Stefanie Kerkhofs, Ryan Castoro, Sreenath Shanker, Karel de Gendt, Kichiya Suzuki, Frank Claessens, Jean Pierre Issa, Marie Claire Orgebin-Crist, Miles F. Wilkinson

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

Abstract

Mammalian male fertility depends on the epididymis, a highly segmented organ that promotes sperm maturation and protects sperm from oxidative damage. Remarkably little is known about how gene expression is controlled in the epididymis. A candidate to regulate genes crucial for epididymal function is reproductive homeobox gene on X chromosome (RHOX)5, a homeobox transcription factor essential for optimal sperm motility that is expressed in the caput region of the epididymis. Here, we report the identification of factors that control Rhox5 gene expression in epididymal cells in a developmentally regulated and region-specific fashion. First, we identify GATA transcription factor-binding sites in the Rhox5 proximal promoter (Pp) necessary for Rhox5 expression in epididymal cells in vitro and in vivo. Adjacent to the GATA sites are androgenresponse elements, which bind to the nuclear hormone receptor androgen receptor (AR), and are responsible for the AR-dependent expression of Rhox5 in epididymal cells. We provide evidence that AR is recruited to the Pp in a region-specific and developmentally regulated manner in the epididymis that is dictated not only by differential AR availability but differential methylation of the Pp. Site-specific methylation of the Pp cytosine and guanine separated by one phosphate, most of which overlap with androgen-response elements, inhibited both AR occupancy at the Pp and Pp-dependent transcription in caput epididymal cells. Together, our data support a model in which DNA methylation, AR, and GATA factors collaborate to dictate the unique developmental and region-specific expression pattern of the RHOX5 homeobox transcription factor in the caput epididymis, which in turn controls the expression of genes critical for promoting sperm motility and function.

Original languageEnglish
Pages (from-to)538-549
Number of pages12
JournalMolecular Endocrinology
Volume26
Issue number4
DOIs
Publication statusPublished - 2012 Apr 1
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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