Department of Biomedical Science, Program in Biomedical Science and Engineering, Department of Physiology and Biophysics, College of Medicine, Inha University, Incheon, Korea.
Department of Life Sciences, Ewha Womans University, Seoul, Korea.
J Pineal Res. 2024 Aug;76(5):e13001. doi: 10.1111/jpi.13001.
This study explores the 24-h rhythmic cycle of protein O-GlcNAcylation within the brain and highlights its crucial role in regulating the circadian cycle and neuronal function based on zebrafish as an animal model. In our experiments, disruption of the circadian rhythm, achieved through inversion of the light-dark cycle or daytime melatonin treatment, not only impaired the rhythmic changes of O-GlcNAcylation along with altering expression patterns of O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) in zebrafish brain but also significantly impeded learning and memory function. In particular, circadian disruption affected rhythmic expression of protein O-GlcNAcylation and OGT in the nuclear fraction. Notably, the circadian cycle induces rhythmic alterations in O-GlcNAcylation of H2B histone protein that correspond to changes in H3 trimethylation. Disruption of the cycle interfered with these periodic histone code alterations. Pharmacological inhibition of OGT with OSMI-1 disrupted the wake-sleep patterns of zebrafish without affecting expression of circadian rhythm-regulating genes. OSMI-1 inhibited the expression of c-fos, bdnf, and calm1, key genes associated with brain function and synaptic plasticity, and decreased the binding of O-GlcNAcylated H2B and OGT to promoter regions of these genes. The collective findings support the potential involvement of circadian cycling of the O-GlcNAc histone code in regulating synaptic plasticity and brain function. Overall, data from this study provide evidence that protein O-GlcNAcylation serves as a pivotal posttranslational mechanism integrating circadian signals and neuronal function to regulate rhythmic physiology.
本研究探索了大脑中蛋白质 O-GlcNAc 修饰的 24 小时节律循环，并基于斑马鱼作为动物模型，强调了其在调节昼夜节律和神经元功能中的关键作用。在我们的实验中，通过颠倒昼夜节律或白天给予褪黑素处理来破坏昼夜节律，不仅破坏了 O-GlcNAc 修饰的节律变化，同时改变了斑马鱼大脑中 O-GlcNAc 转移酶（OGT）和 O-GlcNAcase（OGA）的表达模式，还严重损害了学习和记忆功能。特别是，昼夜节律破坏影响了核蛋白 O-GlcNAc 修饰和 OGT 的节律表达。值得注意的是，昼夜节律诱导 H2B 组蛋白蛋白 O-GlcNAc 修饰的节律变化，与 H3 三甲基化的变化相对应。周期的破坏干扰了这些周期性组蛋白密码的改变。用 OSMI-1 抑制 OGT 会破坏斑马鱼的睡眠-觉醒模式，而不影响昼夜节律调节基因的表达。OSMI-1 抑制了 c-fos、bdnf 和 calm1 等关键基因的表达，这些基因与大脑功能和突触可塑性有关，并降低了 O-GlcNAc 化 H2B 和 OGT 与这些基因启动子区域的结合。这些研究结果表明，O-GlcNAc 组蛋白密码的昼夜循环可能参与调节突触可塑性和大脑功能。总的来说，本研究提供的证据表明，蛋白质 O-GlcNAc 修饰作为一种关键的翻译后机制，整合了昼夜节律信号和神经元功能，以调节节律生理。
