Zhou Rui, Zhang Chaodong, Gan Rui, Yin Xin, Wang Meng, Shi Bihan, Chen Lin, Wu Chongyang, Li Qi, Liu Qinghua
National Institute of Biological Sciences (NIBS), Beijing, China.
School of Life Sciences, Tsinghua University, Beijing, China.
Sleep. 2025 May 12;48(5). doi: 10.1093/sleep/zsae313.
Histone deacetylase HDAC4/5 cooperates with cAMP response element-binding protein (CREB) in the transcriptional regulation of daily sleep amount downstream of LKB1-SIK3 kinase cascade in mice. Here, we report a significant enrichment of the E-box motifs for the basic loop-helix-loop (bHLH) proteins near the CREB- and HDAC4-binding sites in the mouse genome. Adeno-associated virus-mediated expression of class I bHLH transcription factors, such as TCF4, TCF3, or TCF12, across the mouse brain neurons reduces the duration of rapid eye movement sleep (REMS) and non-REMS (NREMS). TCF4 requires its bHLH domain to regulate REMS or NREMS amount, of which the latter is mostly independent of the E-box-binding activity. Consistent with that TCF4 interacts with CREB and HDAC4 via the bHLH domain, TCF4 relies on CREB and partly on HDAC4 to regulate NREMS/REMS amount. Conversely, the ability of CREB to regulate sleep duration also requires its binding to TCF4 and HDAC4. Together, these results indicate that TCF4, HDAC4, and CREB could function cooperatively in the transcriptional regulation of daily sleep amount in mice.
组蛋白去乙酰化酶HDAC4/5与环磷酸腺苷反应元件结合蛋白（CREB）协同作用，在小鼠LKB1-SIK3激酶级联反应下游对每日睡眠量进行转录调控。在此，我们报告在小鼠基因组中，靠近CREB和HDAC4结合位点处，碱性环-螺旋-环（bHLH）蛋白的E-box基序显著富集。腺相关病毒介导的I类bHLH转录因子（如TCF4、TCF3或TCF12）在小鼠脑神经元中的表达可缩短快速眼动睡眠（REMS）和非快速眼动睡眠（NREMS）的时长。TCF4需要其bHLH结构域来调节REMS或NREMS量，其中后者大多独立于E-box结合活性。与TCF4通过bHLH结构域与CREB和HDAC4相互作用一致，TCF4依赖CREB且部分依赖HDAC4来调节NREMS/REMS量。相反，CREB调节睡眠时间的能力也需要其与TCF4和HDAC4结合。总之，这些结果表明TCF4、HDAC4和CREB可能在小鼠每日睡眠量的转录调控中协同发挥作用。
