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

Endocrinology. 2022 Jan 1;163(1):bqab237. doi: 10.1210/endocr/bqab237.


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.

Keywords: ARE; Rhox5; Sertoli; androgen receptor; gene regulation; transcription factors.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 5' Untranslated Regions
  • Androgens / metabolism*
  • Animals
  • DNA Methylation
  • Gene Expression Regulation*
  • Genes, Homeobox
  • Homeodomain Proteins / genetics*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Plasmids / metabolism
  • Promoter Regions, Genetic*
  • Protein Isoforms
  • Receptors, Androgen / metabolism
  • Seminiferous Tubules / metabolism
  • Sertoli Cells / metabolism*
  • Spermatogenesis
  • Testis / metabolism
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism


  • 5' Untranslated Regions
  • Androgens
  • Homeodomain Proteins
  • Protein Isoforms
  • Receptors, Androgen
  • Rhox5 protein, mouse
  • Transcription Factors