Hormone-induced and DNA demethylation-induced relief of a tissue-specific and developmentally regulated block in transcriptional elongation

J Biol Chem. 2014 Dec 19;289(51):35087-101. doi: 10.1074/jbc.M114.615435. Epub 2014 Oct 20.


Genome-wide studies have revealed that genes commonly have a high density of RNA polymerase II just downstream of the transcription start site. This has raised the possibility that genes are commonly regulated by transcriptional elongation, but this remains largely untested in vivo, particularly in vertebrates. Here, we show that the proximal promoter from the Rhox5 homeobox gene recruits polymerase II and begins elongating in all tissues and cell lines that we tested, but it only completes elongation in a tissue-specific and developmentally regulated manner. Relief of the elongation block is associated with recruitment of the elongation factor P-TEFb, the co-activator GRIP1, the chromatin remodeling factor BRG1, and specific histone modifications. We provide evidence that two mechanisms relieve the elongation block at the proximal promoter: demethylation and recruitment of androgen receptor. Together, our findings support a model in which promoter proximal pausing helps confer tissue-specific and developmental gene expression through a mechanism regulated by DNA demethylation-dependent nuclear hormone receptor recruitment.

Keywords: Androgen Receptor; DNA Methylation; Hormone; Testosterone; Transcriptional Elongation; Transcriptional Regulation.

Publication types

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

MeSH terms

  • Androgens / pharmacology
  • Animals
  • Cell Line
  • DNA Methylation*
  • Gene Expression Regulation, Developmental / drug effects*
  • HeLa Cells
  • Histones / metabolism
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Liver / growth & development
  • Liver / metabolism
  • Male
  • Mice
  • Organ Specificity*
  • Positive Transcriptional Elongation Factor B / metabolism
  • Promoter Regions, Genetic / genetics
  • RNA Polymerase II / metabolism
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism
  • Response Elements / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Seminal Vesicles / growth & development
  • Seminal Vesicles / metabolism
  • Testis / growth & development
  • Testis / metabolism
  • Testosterone / pharmacology*
  • Transcription Elongation, Genetic / drug effects*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism


  • Androgens
  • Histones
  • Homeodomain Proteins
  • Receptors, Androgen
  • Transcription Factors
  • Testosterone
  • Positive Transcriptional Elongation Factor B
  • RNA Polymerase II