SelexGLM differentiates androgen and glucocorticoid receptor DNA-binding preference over an extended binding site

Genome Res. 2018 Jan;28(1):111-121. doi: 10.1101/gr.222844.117. Epub 2017 Dec 1.


The DNA-binding interfaces of the androgen (AR) and glucocorticoid (GR) receptors are virtually identical, yet these transcription factors share only about a third of their genomic binding sites and regulate similarly distinct sets of target genes. To address this paradox, we determined the intrinsic specificities of the AR and GR DNA-binding domains using a refined version of SELEX-seq. We developed an algorithm, SelexGLM, that quantifies binding specificity over a large (31-bp) binding site by iteratively fitting a feature-based generalized linear model to SELEX probe counts. This analysis revealed that the DNA-binding preferences of AR and GR homodimers differ significantly, both within and outside the 15-bp core binding site. The relative preference between the two factors can be tuned over a wide range by changing the DNA sequence, with AR more sensitive to sequence changes than GR. The specificity of AR extends to the regions flanking the core 15-bp site, where isothermal calorimetry measurements reveal that affinity is augmented by enthalpy-driven readout of poly(A) sequences associated with narrowed minor groove width. We conclude that the increased specificity of AR is correlated with more enthalpy-driven binding than GR. The binding models help explain differences in AR and GR genomic binding and provide a biophysical rationale for how promiscuous binding by GR allows functional substitution for AR in some castration-resistant prostate cancers.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Androgen Receptor Antagonists* / chemical synthesis
  • Androgen Receptor Antagonists* / chemistry
  • Androgen Receptor Antagonists* / pharmacology
  • Aptamers, Nucleotide / chemical synthesis
  • Aptamers, Nucleotide / chemistry
  • Aptamers, Nucleotide / pharmacology
  • Cell Line, Tumor
  • Humans
  • Male
  • Neoplasm Proteins* / antagonists & inhibitors
  • Neoplasm Proteins* / metabolism
  • Prostatic Neoplasms, Castration-Resistant*
  • Receptors, Androgen / metabolism*
  • Receptors, Glucocorticoid* / antagonists & inhibitors
  • Receptors, Glucocorticoid* / metabolism
  • SELEX Aptamer Technique / methods*


  • Androgen Receptor Antagonists
  • Aptamers, Nucleotide
  • Neoplasm Proteins
  • Receptors, Androgen
  • Receptors, Glucocorticoid