睾丸特异性含溴结构域的蛋白作为潜在男性抗生育药物靶标的研究进展

Research progress of bromodomain-containing protein as male antifertility drug target

哺乳动物的四种含溴结构域蛋白(BET)基因在精子发生不同阶段均有表达,其中睾丸特异表达的bromodomain-containing protein(BRDT)对精子发生必不可少。BRDT在核染色质重组中起关键作用,也参与基因转录和共转录调节。BRDT的第一个溴结构域缺失导致圆形精子细胞错误伸长、精子形态严重缺陷,而圆形精子细胞的错误伸长与减数分裂之后染色质结构异常相关。另外,BRDT是形成圆形精子细胞染色质核仁所必需的;精母细胞和精子细胞缺乏全长的BRDT将会导致转录和可变剪接过程发生改变。动物实验证实一种小分子的BRDT抑制剂(JQ1),具有良好的抗生育作用,这为进一步开发可逆的男性抗生育药物开辟了新思路。

Four kinds of mammalian bromodomain and extra terminal （BET）genes are expressed at unique times during spermatogenesis.Among them,testis-specific bromodomain-containing protein （BRDT）is a testisspecific express protein which essential for spermatogenesis.BRDT is not only essential for proper chromatin or chromatin organization,but also involves in regulation of transcription and co-transcriptional process.Loss of the first bromodomain of BRDT results in incomplete spermatid elongation and severely morphological defect of sperm.The elongation defects observed in mutant spermatids can be directly tied to altered postmeiotic chromatin architecture.Besides,BRDT is required for creation of the chromocenter of round spermatid.Transcription and alternative splicing are altered in spermatocytes and spermatids that lack full-length BRDT.To date,scientists have developed a small molecule inhibitor（JQ1）of BRDT,which have been proved to have good male antifertility effect.It could be useful as reversible male contraceptives.The research results open up a new way for further development of reversible male antifertility drugs.