Dynamic Nucleosome-Depleted Regions at Androgen Receptor Enhancers in the Absence of Ligand in Prostate Cancer Cells
Dynamic Nucleosome-Depleted Regions at Androgen Receptor Enhancers in the Absence of Ligand in Prostate Cancer Cells
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DOI：
10.1128/mcb.05934-11
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发表时间：
2011-12-01
影响因子：
5.3
通讯作者：
Coetzee, Gerhard A.
中科院分区：
文献类型：
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作者：
Andreu-Vieyra, Claudia;Lai, John;Coetzee, Gerhard A.
众所周知，位于转录起始位点的核小体可通过改变 DNA 对转录因子的可及性来调节基因表达。然而，人们对它在增强子中的作用知之甚少。我们研究了前列腺癌细胞中 TMPRSS2、KLK2 和 KLK3/PSA 雄激素受体 (AR) 增强子的核小体定位。令人惊讶的是，雄激素剥夺培养物中的增强子模块群体在所有三个基因座中均显示出核小体耗尽区域（NDR）。在雄激素剥夺条件下，TMPRSS2 增强子上的 NDR 由 AR 转录合作者先驱 GATA-2 维持。雄激素处理导致 AR 占据、具有 NDR 的增强子模块数量增加而足迹宽度没有变化、组蛋白 H3 乙酰化 (AcH3) 水平增加以及 NDR 侧翼核小体的二甲基化 (H3K4me2) 水平增加。我们的数据表明，在没有配体的情况下，AR 增强剂处于平衡状态，其中一定比例的模块被核小体占据，而其他模块则显示 NDR。我们认为雄激素治疗会导致平衡向核小体耗尽状态的破坏，而不是增强从头的“重塑”。这允许招募组蛋白修饰剂、染色质重塑剂，并最终激活基因。这里描述的“接受”状态可以帮助解释在非常低的配体浓度下 AR 信号传导的激活。
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.