小柯机器人

北京生命科学研究所刘清华研究组发现小鼠睡眠量转录调控的一条信号通路。相关论文于2022年12月7日在线发表在《自然》杂志上。

研究人员利用腺相关病毒介导的体细胞遗传学分析，描述了小鼠睡眠转录调节的一条主要信号通路。成年小鼠大脑中LKB1激酶（AMPK相关蛋白激酶SIK3的激活因子）的嵌合敲除，明显减少了非快速眼动睡眠（NREMS）的数量和delta功率（衡量睡眠深度的标准）。在LKB1-SIK3途径的下游，成体大脑神经元中组蛋白去乙酰化酶HDAC4和HDAC5的功能增强或丧失导致NREMS数量和delta功率的双向变化。此外，HDAC4和HDAC5的磷酸化与睡眠需求的增加有关，HDAC4专门调节下丘脑后部的NREMS量。遗传和转录组研究显示，HDAC4在转录和睡眠调节方面与CREB合作。这些发现引入了新的概念——以转录调节因子为目标的信号通路调节每日睡眠量，并证明了体细胞遗传学在小鼠睡眠研究中的力量。

据介绍，在小鼠和人类中，睡眠量受遗传因素的制约，并表现出与年龄有关的变化。然而，调节哺乳动物睡眠时间的核心分子途径和效应机制仍不清楚。

附：英文原文

Title: A signalling pathway for transcriptional regulation of sleep amount in mice

Author: Zhou, Rui, Wang, Guodong, Li, Qi, Meng, Fanxi, Liu, Can, Gan, Rui, Ju, Dapeng, Liao, Meimei, Xu, Junjie, Sang, Di, Gao, Xue, Zhou, Shuang, Wu, Kejia, Sun, Quanzhi, Guo, Ying, Wu, Chongyang, Chen, Zhiyu, Chen, Lin, Shi, Bihan, Wang, Haiyan, Wang, Xia, Li, Huaiye, Cai, Tao, Li, Bin, Wang, Fengchao, Funato, Hiromasa, Yanagisawa, Masashi, Zhang, Eric Erquan, Liu, Qinghua

Issue&Volume: 2022-12-07

Abstract: In mice and humans, sleep quantity is governed by genetic factors and exhibits age-dependent variation1,2,3. However, the core molecular pathways and effector mechanisms that regulate sleep duration in mammals remain unclear. Here, we characterize a major signalling pathway for the transcriptional regulation of sleep in mice using adeno-associated virus-mediated somatic genetics analysis4. Chimeric knockout of LKB1 kinase—an activator of AMPK-related protein kinase SIK35,6,7—in adult mouse brain markedly reduces the amount and delta power—a measure of sleep depth—of non-rapid eye movement sleep (NREMS). Downstream of the LKB1–SIK3 pathway, gain or loss-of-function of the histone deacetylases HDAC4 and HDAC5 in adult brain neurons causes bidirectional changes of NREMS amount and delta power. Moreover, phosphorylation of HDAC4 and HDAC5 is associated with increased sleep need, and HDAC4 specifically regulates NREMS amount in posterior hypothalamus. Genetic and transcriptomic studies reveal that HDAC4 cooperates with CREB in both transcriptional and sleep regulation. These findings introduce the concept of signalling pathways targeting transcription modulators to regulate daily sleep amount and demonstrate the power of somatic genetics in mouse sleep research.

DOI: 10.1038/s41586-022-05510-6

Source: https://www.nature.com/articles/s41586-022-05510-6

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html