Cooperativity and equilibrium with FOXA1 define the androgen receptor transcriptional program.
Cooperativity and equilibrium with FOXA1 define the androgen receptor transcriptional program.
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DOI：
10.1038/ncomms4972
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发表时间：
2014-05-30
影响因子：
16.6
通讯作者：
Yu, Jindan
中科院分区：
文献类型：
--
作者：
Jin, Hong-Jian;Zhao, Jonathan C.;Wu, Longtao;Kim, Jung;Yu, Jindan
先驱因子FOXA 1打开染色质，以促进雄激素受体（AR）与前列腺特异性基因的结合。然而，FOXA 1如何控制AR顺反子组还不完全清楚。在这里，我们表明，AR直接结合染色质通过雄激素反应元件（战神）。FOXA 1不是AR-染色质相互作用所必需的，但有助于通过打开邻近FKHD位点周围的局部染色质将AR募集到低亲和力半ARE。太多的FOXA 1会产生过多的开放染色质区域，这些区域作为储存库，通过丰富的半ARE保留AR，从而降低其对特定位点的可用性。相比之下，FOXA 1下调放弃AR以允许结合基因组中的战神，导致即使在雄激素不存在的情况下也发生大量的AR结合事件和AR靶基因表达。总之，我们的数据说明了与FOXA 1的协同性和平衡性定义AR顺式组的机制细节，并揭示了FOXA 1在抑制AR信号传导和去势抵抗性前列腺癌生长中的先前未知功能。
The pioneering factor FOXA1 opens chromatin to facilitate androgen receptor (AR) binding to prostate-specific genes. How FOXA1 controls the AR cistrome, however, is incompletely understood. Here we show that AR directly binds chromatin through the androgen-response elements (AREs). FOXA1 is not required for AR-chromatin interaction, but instrumental in recruiting AR to low-affinity half-AREs by opening local chromatin around adjacent FKHD sites. Too much FOXA1 creates excessive open chromatin regions, which serve as reservoirs that retain AR via abundant half-AREs, thereby reducing its availability for specific sites. FOXA1 down-regulation, by contrast, relinquishes AR to permissively bind AREs across the genome, resulting in substantial AR binding events and AR-target gene expression even in the absence of androgen. Taken together, our data illustrate the mechanistic details by which cooperativity and equilibrium with FOXA1 define AR cistrome and reveal a previously unknown function of FOXA1 in inhibiting AR signaling and castration-resistant prostate cancer growth.
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