Hu Erling, Du Huan, Shang Sen, Zhang Yali, Lu Xiaoyun
Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Sciences and Technology, Xi'an Jiaotong University, Xi'an, China.
Front Neurosci. 2020 Oct 28;14:591177. doi: 10.3389/fnins.2020.591177. eCollection 2020.
Neurological evidence suggests that beta-hydroxybutyrate (BHBA) has positive effects on the central nervous system. Previous studies have explored the molecular mechanisms by which BHBA affects different brain functions, but the effects of BHBA on epigenetic modifications remain elusive. Here, we showed that BHBA enhanced brain-derived neurotrophic factor (BDNF) expression by increasing H3K4me3 and decreasing H2AK119ub occupancy at the promoters I, II, IV, and VI in hippocampal neurons. Moreover, BHBA treatment induced the upregulation of H3K4me3 and downregulation of H2AK119ub on the global level, both of which were dependent on the L-type calcium channel. Additionally, the BHBA-activated L-type calcium channel subsequently triggered the activation of Ca/CaMKII/CREB signaling, and promoted the binding of p-CREB and CBP to promoters. These results indicate that BHBA regulates cellular signaling and multiple histone modifications to cooperatively modulate BDNF, suggesting a wide range of regulatory effects of BHBA in the central nervous system.
神经学证据表明，β-羟基丁酸（BHBA）对中枢神经系统具有积极作用。以往的研究探讨了BHBA影响不同脑功能的分子机制，但BHBA对表观遗传修饰的影响仍不明确。在此，我们发现BHBA通过增加海马神经元中启动子I、II、IV和VI处的H3K4me3并降低H2AK119ub占有率来增强脑源性神经营养因子（BDNF）的表达。此外，BHBA处理在整体水平上诱导了H3K4me3的上调和H2AK119ub的下调，这两者均依赖于L型钙通道。此外，BHBA激活的L型钙通道随后触发Ca/CaMKII/CREB信号的激活，并促进p-CREB和CBP与启动子的结合。这些结果表明，BHBA调节细胞信号传导和多种组蛋白修饰以协同调节BDNF，提示BHBA在中枢神经系统中具有广泛的调节作用。
