溴尿嘧啶
生物
精子发生
精子细胞
染色质
精母细胞
男性避孕药
组蛋白H4
细胞生物学
组蛋白
内科学
内分泌学
遗传学
人口
减数分裂
基因
计划生育
医学
环境卫生
研究方法
作者
Martin M. Matzuk,Michael R. McKeown,P. Filippakopoulos,Qinglei Li,Lang Ma,Julio E. Agno,Madeleine E. Lemieux,S. Picaud,Richard N. Yu,Jun Qi,Stefan Knapp,James E. Bradner
出处
期刊:Cell
[Elsevier]
日期:2012-08-01
卷期号:150 (4): 673-684
被引量:381
标识
DOI:10.1016/j.cell.2012.06.045
摘要
Summary
A pharmacologic approach to male contraception remains a longstanding challenge in medicine. Toward this objective, we explored the spermatogenic effects of a selective small-molecule inhibitor (JQ1) of the bromodomain and extraterminal (BET) subfamily of epigenetic reader proteins. Here, we report potent inhibition of the testis-specific member BRDT, which is essential for chromatin remodeling during spermatogenesis. Biochemical and crystallographic studies confirm that occupancy of the BRDT acetyl-lysine binding pocket by JQ1 prevents recognition of acetylated histone H4. Treatment of mice with JQ1 reduced seminiferous tubule area, testis size, and spermatozoa number and motility without affecting hormone levels. Although JQ1-treated males mate normally, inhibitory effects of JQ1 evident at the spermatocyte and round spermatid stages cause a complete and reversible contraceptive effect. These data establish a new contraceptive that can cross the blood:testis boundary and inhibit bromodomain activity during spermatogenesis, providing a lead compound targeting the male germ cell for contraception. PaperClip
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