Concordant Androgen-Regulated Expression of Divergent Rhox5 Promoters in Sertoli Cells

Anjana Bhardwaj, Abhishek Sohni, Chih Hong Lou, Karel De Gendt, Fanmao Zhang, Eunah Kim, Panneerdoss Subbarayalu, Waikin Chan, Stefanie Kerkhofs, Frank Claessens, Sarah Kimmins, Manjeet K. Rao, Marvin Meistrich, Miles F. Wilkinson

Research output: Contribution to journalArticlepeer-review

Abstract

Concordant transcriptional regulation can generate multiple gene products that collaborate to achieve a common goal. Here we report a case of concordant transcriptional regulation that instead drives a single protein to be produced in the same cell type from divergent promoters. This gene product-the RHOX5 homeobox transcription factor-is translated from 2 different mRNAs with different 5' untranslated regions (UTRs) transcribed from alternative promoters. Despite the fact that these 2 promoters-the proximal promoter (Pp) and the distal promoter (Pd)-exhibit different patterns of tissue-specific activity, share no obvious sequence identity, and depend on distinct transcription factors for expression, they exhibit a remarkably similar expression pattern in the testes. In particular, both depend on androgen signaling for expression in the testes, where they are specifically expressed in Sertoli cells and have a similar stage-specific expression pattern during the seminiferous epithelial cycle. We report evidence for 3 mechanisms that collaborate to drive concordant Pp/Pd expression. First, both promoters have an intrinsic ability to respond to androgen receptor and androgen. Second, the Pp acts as an enhancer to promote androgen-dependent transcription from the Pd. Third, Pd transcription is positively autoregulated by the RHOX5 protein, which is first produced developmentally from the Pp. Together, our data support a model in which the Rhox5 homeobox gene evolved multiple mechanisms to activate both of its promoters in Sertoli cells to produce Rhox5 in an androgen-dependent manner during different phases of spermatogenesis.

Original languageEnglish (US)
JournalEndocrinology
Volume163
Issue number1
DOIs
StatePublished - Jan 1 2022

Keywords

  • ARE
  • Rhox5
  • Sertoli
  • androgen receptor
  • gene regulation
  • transcription factors

ASJC Scopus subject areas

  • Endocrinology

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