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

Autor:	Zhang L; Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA., Martini GD; Department of Biological Sciences, Columbia University, New York, New York 10027, USA.; Department of Systems Biology, Columbia University Medical Center, New York, New York 10032, USA., Rube HT; Department of Biological Sciences, Columbia University, New York, New York 10027, USA.; Department of Systems Biology, Columbia University Medical Center, New York, New York 10032, USA., Kribelbauer JF; Department of Biological Sciences, Columbia University, New York, New York 10027, USA.; Department of Systems Biology, Columbia University Medical Center, New York, New York 10032, USA., Rastogi C; Department of Biological Sciences, Columbia University, New York, New York 10027, USA.; Department of Systems Biology, Columbia University Medical Center, New York, New York 10032, USA., FitzPatrick VD; Department of Biological Sciences, Columbia University, New York, New York 10027, USA.; Department of Systems Biology, Columbia University Medical Center, New York, New York 10032, USA., Houtman JC; Department of Immunology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA., Bussemaker HJ; Department of Biological Sciences, Columbia University, New York, New York 10027, USA.; Department of Systems Biology, Columbia University Medical Center, New York, New York 10032, USA., Pufall MA; Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
Jazyk:	angličtina
Zdroj:	Genome research [Genome Res] 2018 Jan; Vol. 28 (1), pp. 111-121. Date of Electronic Publication: 2017 Dec 01.
DOI:	10.1101/gr.222844.117
Abstrakt:	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. (© 2018 Zhang et al.; Published by Cold Spring Harbor Laboratory Press.)
Databáze:	MEDLINE
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