title: Agonist and antagonist switch DNA motifs recognized by human androgen receptor in prostate cancer.
abstract: Human transcription factors recognize specific DNA sequence motifs to regulate transcription. It is unknown whether a single transcription factor is able to bind to distinctly different motifs on chromatin, and if so, what determines the usage of specific motifs. By using a motif-resolution chromatin immunoprecipitation-exonuclease (ChIP-exo) approach, we find that agonist-liganded human androgen receptor (AR) and antagonist-liganded AR bind to two distinctly different motifs, leading to distinct transcriptional outcomes in prostate cancer cells. Further analysis on clinical prostate tissues reveals that the binding of AR to these two distinct motifs is involved in prostate carcinogenesis. Together, these results suggest that unique ligands may switch DNA motifs recognized by ligand-dependent transcription factors in vivo. Our findings also provide a broad mechanistic foundation for understanding ligand-specific induction of gene expression profiles.
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics and the Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH, USA.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Biomedical Informatics, The Ohio State University College of Medicine, Columbus, OH, USA.
authors.forename: Xun
authors.initials: X
authors.lastname: Lan
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine and the Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Thomas-Ahner
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics and the Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH, USA.
authors.forename: Dayong
authors.initials: D
authors.lastname: Wu
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics and the Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH, USA.
authors.forename: Xiangtao
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Biomedical Informatics, The Ohio State University College of Medicine, Columbus, OH, USA Department of Molecular Medicine, Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Zhenqing
authors.initials: Z
authors.lastname: Ye
authors.affiliation: Division of Biostatistics, Dan L. Duncan Cancer Center Baylor College of Medicine, Houston, TX, USA Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Liguo
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics and the Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Sunkel
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics and the Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH, USA.
authors.forename: Cassandra
authors.initials: C
authors.lastname: Grenade
authors.affiliation: Division of Biostatistics, Dan L. Duncan Cancer Center Baylor College of Medicine, Houston, TX, USA Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Junsheng
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Pathology, The Ohio State University College of Medicine, Columbus, OH, USA.
authors.forename: Debra L
authors.initials: DL
authors.lastname: Zynger
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics and the Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH, USA.
authors.forename: Pearlly S
authors.initials: PS
authors.lastname: Yan
authors.affiliation: Departments of Pathology and Urology, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA Broad Center for Regenerative Medicine and Stem Cell Research, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors.forename: Jiaoti
authors.initials: J
authors.lastname: Huang
authors.affiliation: Medical Sciences Program, Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Bloomington, IN, USA.
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Nephew
authors.affiliation: Department of Molecular Medicine, Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Tim H-M
authors.initials: TH
authors.lastname: Huang
authors.affiliation: Department of Statistics, The Ohio State University, Columbus, OH, USA.
authors.forename: Shili
authors.initials: S
authors.lastname: Lin
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine and the Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH, USA.
authors.forename: Steven K
authors.initials: SK
authors.lastname: Clinton
authors.affiliation: Division of Biostatistics, Dan L. Duncan Cancer Center Baylor College of Medicine, Houston, TX, USA Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Biomedical Informatics, The Ohio State University College of Medicine, Columbus, OH, USA Department of Molecular Medicine, Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Victor X
authors.initials: VX
authors.lastname: Jin
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics and the Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH, USA qianben.wang@osumc.edu.
authors.forename: Qianben
authors.initials: Q
authors.lastname: Wang
mesh_terms: D059002:Androgen Receptor Antagonists / Q000737:chemistry* / Q000378:metabolism; D000728:Androgens / Q000737:chemistry* / Q000378:metabolism; D049109:Cell Proliferation / Q000502:physiology; D047369:Chromatin Immunoprecipitation; D004247:DNA / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C410798:AR protein, human; D059002:Androgen Receptor Antagonists; D000728:Androgens; D011944:Receptors, Androgen; D004247:DNA
keywords: ChIP‐exo; DNA motif switching; androgen receptor; prostate cancer; transcription factor