Journal article
SelexGLM differentiates androgen and glucocorticoid receptor DNA-binding preference over an extended binding site
Genome research, Vol.28(1), pp.111-121
01/2018
DOI: 10.1101/gr.222844.117
PMCID: PMC5749176
PMID: 29196557
Abstract
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.
Details
- Title: Subtitle
- SelexGLM differentiates androgen and glucocorticoid receptor DNA-binding preference over an extended binding site
- Creators
- Liyang Zhang - Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USAGabriella D Martini - Department of Biological Sciences, Columbia University, New York, New York 10027, USAH. Tomas Rube - Department of Biological Sciences, Columbia University, New York, New York 10027, USAJudith F Kribelbauer - Department of Biological Sciences, Columbia University, New York, New York 10027, USAChaitanya Rastogi - Department of Biological Sciences, Columbia University, New York, New York 10027, USAVincent D FitzPatrick - Department of Biological Sciences, Columbia University, New York, New York 10027, USAJon C Houtman - Department of Immunology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USAHarmen J Bussemaker - Department of Biological Sciences, Columbia University, New York, New York 10027, USAMiles A Pufall - Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA
- Resource Type
- Journal article
- Publication Details
- Genome research, Vol.28(1), pp.111-121
- Publisher
- Cold Spring Harbor Laboratory Press
- DOI
- 10.1101/gr.222844.117
- PMID
- 29196557
- PMCID
- PMC5749176
- ISSN
- 1088-9051
- eISSN
- 1549-5469
- Grant note
- ; 1552862; R01HG003008 / ; K99/R00 CA149088 / ; 01-224 / ;
- Alternative title
- Zhang et al
- Language
- English
- Date published
- 01/2018
- Academic Unit
- Microbiology and Immunology; Biochemistry and Molecular Biology; Internal Medicine
- Record Identifier
- 9984094345702771
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