10月13日，內(nèi)分泌領(lǐng)域權(quán)威期刊Molecular Endocrinology雜志在線發(fā)表了上海生科院生化與細(xì)胞所張永蓮研究組取得的最新研究成果：雄激素受體在小鼠附睪基因組結(jié)合位點(diǎn)的鑒定,。
附睪結(jié)構(gòu)和功能的維持以及基因表達(dá)均高度依賴于雄激素,，雄激素的作用是由雄激素受體（AR）結(jié)合于雄激素應(yīng)答元件完成的。附睪是體內(nèi)雄激素受體表達(dá)量最高的幾個(gè)器官之一,。通過cDNA芯片研究已經(jīng)鑒定到很多附睪表達(dá)的基因受雄激素調(diào)控,，但目前為止，AR在附睪內(nèi)的直接靶基因仍然所知甚少,。
博士研究生胡雙綱等人在張永蓮院士和劉強(qiáng)副研究員指導(dǎo)下,，利用ChIP-seq的方法檢測(cè)了小鼠頭部附睪（AR高表達(dá)）中的基因組水平的AR結(jié)合位點(diǎn)。該方法鑒定了總共19377個(gè)AR結(jié)合位點(diǎn),，其中絕大部分位于基因間區(qū)域和內(nèi)含子區(qū)域,，只有7%的結(jié)合位點(diǎn)位于轉(zhuǎn)錄起始位點(diǎn)上游5kb的區(qū)域內(nèi)。這些AR結(jié)合位點(diǎn)共關(guān)聯(lián)了8190個(gè)靶基因,，參與了廣泛的生理過程,。Motif分析顯示多達(dá)94%的AR結(jié)合位點(diǎn)含有保守的雄激素應(yīng)答元件，一些潛在的協(xié)同因子結(jié)合的motifs也在雄激素應(yīng)答元件附近得到了顯著富集,，其中包括了之前已經(jīng)報(bào)道過的NF1位點(diǎn)和新發(fā)現(xiàn)的AP-2位點(diǎn), 暗示了NF1,，AP-2和AR之間的協(xié)同調(diào)控。令人驚訝的是這些結(jié)合位點(diǎn)在物種間保守性不高,。該研究也在單基因水平闡明了雄激素受體對(duì)某些附睪基因表達(dá)調(diào)控的新機(jī)制,。
本工作首次揭示了雄激素受體在生理?xiàng)l件下的基因組結(jié)合位點(diǎn)的圖譜，使我們對(duì)AR在生理狀態(tài)下在頭部附睪內(nèi)的調(diào)控網(wǎng)絡(luò)有了一個(gè)更深刻的認(rèn)識(shí),。同時(shí)也是對(duì)之前在前列腺癌細(xì)胞系和原代肌細(xì)胞等非生理?xiàng)l件下AR結(jié)合位點(diǎn)的研究數(shù)據(jù)的一個(gè)有力補(bǔ)充和擴(kuò)展,。
該研究工作得到國家科技部,、國家自然科學(xué)基金委,，中國科學(xué)院和美國NIH的經(jīng)費(fèi)資助,。（生物谷Bioon.com）
生物谷推薦英文摘要：
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.
