Kruppel homolog 1 represses insect ecdysone biosynthesis by directly inhibiting the transcription of steroidogenic enzymes
Kruppel homolog 1 represses insect ecdysone biosynthesis by directly inhibiting the transcription of steroidogenic enzymes
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Krüppel 同源物 1 通过直接抑制类固醇生成酶的转录来抑制昆虫蜕皮激素生物合成
DOI：
10.1073/pnas.1800435115
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发表时间：
2018
期刊：
影响因子：
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通讯作者：
Daojun Cheng
中科院分区：
文献类型：
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作者：
Tianlei Zhang;Wei Song;Zheng Li;Wenliang Qian;Ling Wei;Yan Yang;Weina Wang;Xuan Zhou;Meng Meng;Jian Peng;Qingyou Xia;Norbert Perrimon;Daojun Cheng
意义 昆虫体内的两种主要内分泌激素，保幼激素 (JH) 和蜕皮激素，以相反的方式调节发育转变和生长持续时间。破译 JH 和蜕皮激素之间相互作用的机制是了解昆虫生长和发育控制的关键。我们发现，在果蝇和家蚕中，JH 直接作用于前胸腺，诱导 Krüppel 同源物 1 (Kr-h1) 表达，从而通过减少类固醇生成酶的转录来抑制蜕皮激素生物合成。这种转录抑制是通过 Kr-h1 与靶基因启动子区域的直接结合介导的，从而诱导表观遗传启动子 DNA 甲基化。我们的研究结果为昆虫前胸腺中 Kr-h1 介导的 JH 信号传导直接抑制蜕皮激素生物合成提供了见解。在昆虫中，保幼激素（JH）和类固醇激素蜕皮激素对幼虫-蛹过渡的调节具有相反的作用。尽管越来越多的证据表明 JH 在幼虫发育过程中抑制蜕皮激素生物合成，但这种抑制的机制尚不清楚。在这里，我们证明，Krüppel 同源物 1 (Kr-h1) 是一种编码介导 JH 信号传导的转录因子的基因，在蜕皮激素产生器官前胸腺 (PG) 中的表达通过直接抑制果蝇和家蚕中类固醇生成酶的转录来抑制蜕皮激素生物合成。将 JH 模拟物应用于离体培养的果蝇和家蚕幼虫 PG 上可诱导 Kr-h1 表达并抑制类固醇生成酶的转录。此外，果蝇 Kr-h1 的 PG 特异性敲低可促进（而过度表达会阻碍）蜕皮激素的产生和化蛹。我们进一步发现，Kr-h1 通过直接结合类固醇生成酶的启动子诱导启动子 DNA 甲基化来抑制类固醇生成酶的转录。最后，我们表明 Kr-h1 不影响果蝇 PG 细胞中的 DNA 复制，并且 Kr-h1 过表达介导的 PG 大小的减小可以通过喂食蜕皮激素来挽救。总而言之，我们的数据表明，响应 JH 刺激，Kr-h1 对昆虫蜕皮激素生物合成的直接和保守抑制，为 JH 和蜕皮激素拮抗作用的机制提供了见解。
Significance Two major endocrine hormones in insects, juvenile hormone (JH) and ecdysone, regulate developmental transitions and growth duration in an opposite manner. Deciphering the mechanisms underlying cross-talk between JH and ecdysone is key to understanding the control of insect growth and development. We show that in both Drosophila and Bombyx, JH directly acts on the prothoracic gland to induce Krüppel homolog 1 (Kr-h1) expression, which in turn represses ecdysone biosynthesis by reducing the transcription of steroidogenic enzymes. This transcriptional repression is mediated by direct binding of Kr-h1 to target gene-promoter regions, inducing epigenetic promoter DNA methylation. Our findings provide insights into the direct repression of ecdysone biosynthesis by Kr-h1–mediated JH signaling in insect prothoracic gland. In insects, juvenile hormone (JH) and the steroid hormone ecdysone have opposing effects on regulation of the larval–pupal transition. Although increasing evidence suggests that JH represses ecdysone biosynthesis during larval development, the mechanism underlying this repression is not well understood. Here, we demonstrate that the expression of the Krüppel homolog 1 (Kr-h1), a gene encoding a transcription factor that mediates JH signaling, in ecdysone-producing organ prothoracic gland (PG) represses ecdysone biosynthesis by directly inhibiting the transcription of steroidogenic enzymes in both Drosophila and Bombyx. Application of a JH mimic on ex vivo cultured PGs from Drosophila and Bombyx larvae induces Kr-h1 expression and inhibits the transcription of steroidogenic enzymes. In addition, PG-specific knockdown of Drosophila Kr-h1 promotes—while overexpression hampers—ecdysone production and pupariation. We further find that Kr-h1 inhibits the transcription of steroidogenic enzymes by directly binding to their promoters to induce promoter DNA methylation. Finally, we show that Kr-h1 does not affect DNA replication in Drosophila PG cells and that the reduction of PG size mediated by Kr-h1 overexpression can be rescued by feeding ecdysone. Taken together, our data indicate direct and conserved Kr-h1 repression of insect ecdysone biosynthesis in response to JH stimulation, providing insights into mechanisms underlying the antagonistic roles of JH and ecdysone.