The Histone Demethylase KDM5 Is Essential for Larval Growth in Drosophila.
The Histone Demethylase KDM5 Is Essential for Larval Growth in Drosophila.
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DOI：
10.1534/genetics.118.301004
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发表时间：
2018-07
期刊：
影响因子：
3.3
通讯作者：
Secombe J
中科院分区：
文献类型：
--
作者：
Drelon C;Belalcazar HM;Secombe J
调节基因表达对于发育和稳态过程是必要的。 KDM5 转录调节因子家族是组蛋白 H3 赖氨酸 4 去甲基化酶，可以通过去甲基化酶依赖性和非依赖性机制发挥作用。虽然 KDM5 蛋白的缺失和过度表达分别与智力障碍和癌症相关，但其正常发育功能的特征仍然较少。黑腹果蝇为研究 KDM5 功能提供了一个理想的系统，因为它编码单个直向同源物，而不是在哺乳动物细胞中发现的四个旁系同源物。为了检查 KDM5 完全丢失的后果，我们生成了果蝇 kdm5 的无效等位基因，也称为小成虫盘（盖子），并表明它对于生存至关重要。缺乏 KDM5 的动物表现出幼虫发育显着延迟，同时伴随着翅成虫盘增殖减少和细胞死亡增加。有趣的是，这种发育延迟与 KDM5 已充分表征的 Jumonji C (JmjC) 结构域编码的组蛋白去甲基酶活性无关，这表明特征较少的结构域具有关键功能。与观察到的表型一致，kdm5 缺失突变体翼成虫盘的转录组分析揭示了参与多种细胞过程（包括细胞周期进展和 DNA 修复）的基因失调。总之，我们的分析表明 KDM5 是幼虫生长的关键调节因子，并为定义 KDM5 家族蛋白的生物活性提供了宝贵的工具。
Regulated gene expression is necessary for developmental and homeostatic processes. The KDM5 family of transcriptional regulators are histone H3 lysine 4 demethylases that can function through both demethylase-dependent and -independent mechanisms. While loss and overexpression of KDM5 proteins are linked to intellectual disability and cancer, respectively, their normal developmental functions remain less characterized. Drosophila melanogaster provides an ideal system to investigate KDM5 function, as it encodes a single ortholog in contrast to the four paralogs found in mammalian cells. To examine the consequences of complete loss of KDM5, we generated a null allele of Drosophila kdm5, also known as little imaginal discs (lid), and show that it is essential for viability. Animals lacking KDM5 show a dramatically delayed larval development that coincides with decreased proliferation and increased cell death in wing imaginal discs. Interestingly, this developmental delay is independent of the well-characterized Jumonji C (JmjC) domain-encoded histone demethylase activity of KDM5, suggesting key functions for less characterized domains. Consistent with the phenotypes observed, transcriptome analyses of kdm5 null mutant wing imaginal discs revealed the dysregulation of genes involved in several cellular processes, including cell cycle progression and DNA repair. Together, our analyses reveal KDM5 as a key regulator of larval growth and offer an invaluable tool for defining the biological activities of KDM5 family proteins.