College of Life Sciences, Beijing Normal University, Beijing 100875, China; National Institute of Biological Sciences, Beijing 102206, China; Hubei Engineering Research Center of Special Wild Vegetables Breeding and Comprehensive Utilization Technology, Hubei Key Laboratory of Edible Wild Plants Conservation and Utilization, School of Life Sciences, Hubei Normal University, Huangshi, Hubei Province 435002, China.
College of Life Sciences, Beijing Normal University, Beijing 100875, China; National Institute of Biological Sciences, Beijing 102206, China; Department of Anesthesiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China; Department of Neurosurgery, Xinqiao Hospital, Chongqing 400038, China.
Cell Rep. 2022 May 17;39(7):110816. doi: 10.1016/j.celrep.2022.110816.
The Qinghai-Tibet Plateau (QTP) harbors hundreds of species well adapted to its extreme conditions, including its low-oxygen (hypoxic) atmosphere. Here, we show that the plateau pika-a keystone mammal of the QTP-lacks robust circadian rhythms. The major form of the plateau pika Epas1 protein includes a 24-residue insert caused by a point mutation at the 5' juncture site of Intron14 and is more stable than other mammalian orthologs. Biochemical studies reveal that an Epas1-Bmal1 complex with lower trans-activation activity occupies the E1/E2 motifs at the promoter of the core-clock gene Per2, thus explaining how an Epas1 mutation-selected in the hypoxic conditions of the QTP-disrupts the molecular clockwork. Importantly, experiments with hypoxic chambers show that mice expressing the plateau pika Epas1 ortholog in their suprachiasmatic nucleus have dysregulated central clocks, and pika Epas1 knockin mice reared in hypoxic conditions exhibit dramatically reduced heart damage compared with wild-type animals.
青藏高原（QTP）拥有数百种适应其极端条件的物种，包括低氧（缺氧）环境。在这里，我们表明高原鼠兔——青藏高原的关键哺乳动物——缺乏稳健的昼夜节律。高原鼠兔 Epas1 蛋白的主要形式包括一个 24 个残基的插入，这是由于 14 号内含子 5' 连接点的点突变引起的，比其他哺乳动物同源物更稳定。生化研究表明，一种 Epas1-Bmal1 复合物具有较低的转录激活活性，占据核心时钟基因 Per2 启动子上的 E1/E2 基序，从而解释了高原特有的 Epas1 突变如何在 QTP 的低氧环境中破坏分子钟。重要的是，缺氧室实验表明，在其视交叉上核中表达高原鼠兔 Epas1 同源物的小鼠中心时钟失调，并且在低氧条件下饲养的具有鼠兔 Epas1 基因敲入的小鼠与野生型动物相比，心脏损伤明显减少。
