Effects of long term antiprogestine mifepristone (RU486) exposure on sexually dimorphic lncRNA expression and gonadal masculinization in Nile tilapia (Oreochromis niloticus)
Effects of long term antiprogestine mifepristone (RU486) exposure on sexually dimorphic lncRNA expression and gonadal masculinization in Nile tilapia (Oreochromis niloticus)
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长期暴露于抗孕酮米非司酮 (RU486) 对尼罗罗非鱼 (Oreochromis niloticus) 性二态性 lncRNA 表达和性腺雄性化的影响
DOI：
10.1016/j.aquatox.2019.105289
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发表时间：
2019-10-01
影响因子：
4.5
通讯作者：
Wang, Deshou
中科院分区：
文献类型：
--
作者：
Cai, Jing;Li, Lu;Wang, Deshou
米非司酮（RU 486）是一种临床流产剂和潜在的内分泌干扰物，与孕酮和糖皮质激素受体结合，在生殖生理学中具有多种功能重要性。长期暴露于RU 486导致雌性鱼类雄性化，然而，表观遗传景观仍然难以捉摸。最近的研究表明，长链非编码RNA（lncRNA）可能在性分化、卵巢癌和生殖干细胞存活的表观遗传调控中发挥潜在的作用。为了进一步了解RU 486暴露对表观遗传调控的影响，我们使用对照XX/XY和RU 486诱导的性逆转XX尼罗罗非鱼（Oreochromis niloticus）通过RNA-seq对性别偏向性腺lncRNA谱进行了比较研究。总共从对照和性反转鱼的性腺中筛选出962个性差异表达的lncRNA及其靶基因。与对照XX组相比，RU 486处理诱导的性逆转导致757个lncRNA显著上调，221个lncRNA显著下调。系统聚类分析显示，RU 486处理组XX与对照组XY的lncRNA表达谱聚为同一分支，而XX对照组形成一个单独的分支。KEGG途径富集分析表明，RU 486-XX与对照XX之间的顺式靶基因主要集中在NOD样受体信号通路、细胞粘附分子（CAM）和氨基酸生物合成等方面。实时荧光定量PCR和原位杂交实验表明，在RU 486处理过程中表现出强烈波动的lncRNA在性分化早期也表现出性二态性，进一步证明了lncRNA与性分化和性转分化的密切关系。综上所述，我们的数据强烈表明，长期暴露于RU 486导致XX雌性鱼的性逆转，性二态性lncRNA的表达改变可能通过表观遗传修饰部分解释了性逆转。
Mifepristone (RU486), a clinical abortion agent and potential endocrine disruptor, binds to progestin and glucocorticoid receptors and has multiple functional importance in reproductive physiology. A long-term exposure of RU486 resulted in masculinization of female fish, however, the epigenetic landscape remains elusive. Recent studies demonstrated that long non-coding RNAs (lncRNAs) might play potential roles in epigenetic modulation of sex differentiation, ovarian cancer and germline stem cell survival. To further understand the influence of RU486 exposure on epigenetic regulation, we performed a comparative investigation on sex-biased gonadal lncRNAs profiles using control XX/XY and RU486-induced sex reversed XX Nile tilapia (Oreochromis niloticus) by RNA-seq. In total, 962 sexually differentially expressed lncRNAs and their target genes were screened from the gonads of control and sex reversed fish. In comparison with the control XX group, sex reversal induced by RU486 treatment led to significant up-regulation of 757 lncRNAs and down-regulation of 221 lncRNAs. Hierarchical clustering analysis revealed that global lncRNA expression profiles in RU486-treated XX group clustered into the same branch with the control XY, whereas XX control group formed a separate branch. The KEGG pathway enrichment analysis showed that the cis-target genes between RU486-XX and control-XX were concentrated in NOD - like receptor signaling pathway, Cell adhesion molecules (CAMs) and Biosynthesis of amino acids. Real-time PCR and in situ hybridization experiments demonstrate that lncRNAs showing intense fluctuation during RU486 treatment are also sexually dimorphic during early sex differentiation, which further proves the intimate relationship between lncRNAs and sex differentiation and sexual transdifferentiation. Taken together, our data strongly indicates that a long-term exposure of RU486 resulted in sex reversal of XX female fish and the altered expression of sexually dimorphic lncRNAs might partially account for the sex reversal via epigenetic modification.