Cakouros Dimitrios, Mills Kathryn, Denton Donna, Paterson Alicia, Daish Tasman, Kumar Sharad
Hanson Institute, Institute of Medical and Veterinary Science, Adelaide SA 5000, Australia.
J Cell Biol. 2008 Aug 11;182(3):481-95. doi: 10.1083/jcb.200712169.
The sequential modifications of histones form the basis of the histone code that translates into either gene activation or repression. Nuclear receptors recruit a cohort of histone-modifying enzymes in response to ligand binding and regulate proliferation, differentiation, and cell death. In Drosophila melanogaster, the steroid hormone ecdysone binds its heterodimeric receptor ecdysone receptor/ultraspiracle to spatiotemporally regulate the transcription of several genes. In this study, we identify a novel cofactor, Drosophila lysine ketoglutarate reductase (dLKR)/saccharopine dehydrogenase (SDH), that is involved in ecdysone-mediated transcription. dLKR/SDH binds histones H3 and H4 and suppresses ecdysone-mediated transcription of cell death genes by inhibiting histone H3R17me2 mediated by the Drosophila arginine methyl transferase CARMER. Our data suggest that the dynamic recruitment of dLKR/SDH to ecdysone-regulated gene promoters controls the timing of hormone-induced gene expression. In the absence of dLKR/SDH, histone methylation occurs prematurely, resulting in enhanced gene activation. Consistent with these observations, the loss of dLKR/SDH in Drosophila enhances hormone-regulated gene expression, affecting the developmental timing of gene activation.
组蛋白的序列修饰构成了组蛋白密码的基础，该密码可转化为基因激活或抑制。核受体在配体结合后招募一组组蛋白修饰酶，并调节细胞增殖、分化和细胞死亡。在黑腹果蝇中，类固醇激素蜕皮激素与其异二聚体受体蜕皮激素受体/超气门蛋白结合，以时空方式调节多个基因的转录。在本研究中，我们鉴定出一种新型辅因子，果蝇赖氨酸酮戊二酸还原酶（dLKR）/酵母氨酸脱氢酶（SDH），它参与蜕皮激素介导的转录。dLKR/SDH与组蛋白H3和H4结合，并通过抑制果蝇精氨酸甲基转移酶CARMER介导的组蛋白H3R17me2来抑制蜕皮激素介导的细胞死亡基因转录。我们的数据表明，dLKR/SDH向蜕皮激素调节的基因启动子的动态募集控制着激素诱导基因表达的时间。在没有dLKR/SDH的情况下，组蛋白甲基化过早发生，导致基因激活增强。与这些观察结果一致，果蝇中dLKR/SDH的缺失增强了激素调节的基因表达，影响了基因激活的发育时间。
