title: Dynamic nucleosome-depleted regions at androgen receptor enhancers in the absence of ligand in prostate cancer cells.
abstract: Nucleosome positioning at transcription start sites is known to regulate gene expression by altering DNA accessibility to transcription factors; however, its role at enhancers is poorly understood. We investigated nucleosome positioning at the androgen receptor (AR) enhancers of TMPRSS2, KLK2, and KLK3/PSA in prostate cancer cells. Surprisingly, a population of enhancer modules in androgen-deprived cultures showed nucleosome-depleted regions (NDRs) in all three loci. Under androgen-deprived conditions, NDRs at the TMPRSS2 enhancer were maintained by the pioneer AR transcriptional collaborator GATA-2. Androgen treatment resulted in AR occupancy, an increased number of enhancer modules with NDRs without changes in footprint width, increased levels of histone H3 acetylation (AcH3), and dimethylation (H3K4me2) at nucleosomes flanking the NDRs. Our data suggest that, in the absence of ligand, AR enhancers exist in an equilibrium in which a percentage of modules are occupied by nucleosomes while others display NDRs. We propose that androgen treatment leads to the disruption of the equilibrium toward a nucleosome-depleted state, rather than to enhancer de novo "remodeling." This allows the recruitment of histone modifiers, chromatin remodelers, and ultimately gene activation. The "receptive" state described here could help explain AR signaling activation under very low ligand concentrations.
authors.affiliation: Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Andreu-Vieyra
authors.forename: John
authors.initials: J
authors.lastname: Lai
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Berman
authors.forename: Baruch
authors.initials: B
authors.lastname: Frenkel
authors.forename: Li
authors.initials: L
authors.lastname: Jia
authors.forename: Peter A
authors.initials: PA
authors.lastname: Jones
authors.forename: Gerhard A
authors.initials: GA
authors.lastname: Coetzee
mesh_terms: D000107:Acetylation; D000123:Acetyltransferases / Q000378:metabolism; D000728:Androgens / Q000494:pharmacology / Q000502:physiology; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D018899:CpG Islands; D013196:Dihydrotestosterone / Q000494:pharmacology; D004742:Enhancer Elements, Genetic; D050989:GATA2 Transcription Factor / Q000378:metabolism; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008297:Male; D008745:Methylation; D008780:Methyltransferases / Q000378:metabolism; D009707:Nucleosomes / Q000235:genetics / Q000378:metabolism*; D017430:Prostate-Specific Antigen / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms; D011944:Receptors, Androgen / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D020840:Tissue Kallikreins / Q000235:genetics / Q000378:metabolism
chemical_list: D000728:Androgens; D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; D006657:Histones; D008024:Ligands; D009707:Nucleosomes; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D008780:Methyltransferases; D000123:Acetyltransferases; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human; D020840:Tissue Kallikreins; D017430:Prostate-Specific Antigen