10月13日，内分泌领域权威期刊Molecular Endocrinology杂志在线发表了上海生科院生化与细胞所张永莲研究组取得的最新研究成果：雄激素受体在小鼠附睾基因组结合位点的鉴定。
附睾结构和功能的维持以及基因表达均高度依赖于雄激素，雄激素的作用是由雄激素受体（AR）结合于雄激素应答元件完成的。附睾是体内雄激素受体表达量最高的几个器官之一。通过cDNA芯片研究已经鉴定到很多附睾表达的基因受雄激素调控，但目前为止，AR在附睾内的直接靶基因仍然所知甚少。
博士研究生胡双纲等人在张永莲院士和刘强副研究员指导下，利用ChIP-seq的方法检测了小鼠头部附睾（AR高表达）中的基因组水平的AR结合位点。该方法鉴定了总共19377个AR结合位点，其中绝大部分位于基因间区域和内含子区域，只有7%的结合位点位于转录起始位点上游5kb的区域内。这些AR结合位点共关联了8190个靶基因，参与了广泛的生理过程。Motif分析显示多达94%的AR结合位点含有保守的雄激素应答元件，一些潜在的协同因子结合的motifs也在雄激素应答元件附近得到了显着富集，其中包括了之前已经报道过的NF1位点和新发现的AP-2位点, 暗示了NF1，AP-2和AR之间的协同调控。令人惊讶的是这些结合位点在物种间保守性不高。该研究也在单基因水平阐明了雄激素受体对某些附睾基因表达调控的新机制。
本工作首次揭示了雄激素受体在生理条件下的基因组结合位点的图谱，使我们对AR在生理状态下在头部附睾内的调控网络有了一个更深刻的认识。同时也是对之前在前列腺癌细胞系和原代肌细胞等非生理条件下AR结合位点的研究数据的一个有力补充和扩展。
该研究工作得到国家科技部、国家自然科学基金委，中国科学院和美国NIH的经费资助。（生物谷Bioon.com）
生物谷推荐英文摘要：
Molecular Endocrinology, doi:10.1210/me.2010-0226
Research Resource: Genome-Wide Mapping of in Vivo Androgen Receptor Binding Sites in Mouse Epididymis
Shuanggang Hu, Guangxin Yao, Xiaojun Guan, Zimei Ni, Wubin Ma, Elizabeth M. Wilson, Frank S. French, Qiang Liu*, and Yonglian Zhang*
Shanghai Key Laboratory for Molecular Andrology (S.H., G.Y., Z.N., W.M., Q.L., Y.Z.), State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, The Graduate School (S.H., W.M.), Chinese Academy of Sciences, Shanghai 20031, China; Shanghai Institute of Planned Parenthood Research (Y.Z.), Shanghai 200032, China; Center for Bioinformatics (X.G.) and Laboratories for Reproductive Biology (E.M.W., F.S.F.), Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599; and School of Life Science and Biopharmaceutics (G.Y.), Shenyang Pharmaceutical University, Shenyang, Liaoning Province 110016, China
Epididymal function depends on androgen signaling through the androgen receptor (AR), although most of the direct AR target genes in epididymis remain unknown. Here we globally mapped the AR binding regions in mouse caput epididymis in which AR is highly expressed. Chromatin immunoprecipitation sequencing indicated that AR bound selectively to 19,377 DNA regions, the majority of which were intergenic and intronic. Motif analysis showed that 94% of the AR binding regions harbored consensus androgen response elements enriched with multiple binding motifs that included nuclear factor 1 and activator protein 2 sites consistent with combinatorial regulation. Unexpectedly, AR binding regions showed limited conservation across species, regardless of whether the metric for conservation was based on local sequence similarity or the presence of consensus androgen response elements. Further analysis suggested the AR target genes are involved in diverse biological themes that include lipid metabolism and sperm maturation. Potential novel mechanisms of AR regulation were revealed at individual genes such as cysteine-rich secretory protein 1. The composite studies provide new insights into AR regulation under physiological conditions and a global resource of AR binding sites in a normal androgen-responsive tissue.
