Louma G. Laboratory of Epigenetic Research, Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
Faculty of Life and Environmental Sciences, University of Iceland, Reykjavik, Iceland.
Cell Rep. 2024 Aug 27;43(8):114554. doi: 10.1016/j.celrep.2024.114554. Epub 2024 Jul 30.
The mild hypothermia response (MHR) maintains organismal homeostasis during cold exposure and is thought to be critical for the neuroprotection documented with therapeutic hypothermia. To date, little is known about the transcriptional regulation of the MHR. We utilize a forward CRISPR-Cas9 mutagenesis screen to identify the histone lysine methyltransferase SMYD5 as a regulator of the MHR. SMYD5 represses the key MHR gene SP1 at euthermia. This repression correlates with temperature-dependent levels of histone H3 lysine 26 trimethylation (H3K36me3) at the SP1 locus and globally, indicating that the mammalian MHR is regulated at the level of histone modifications. We have identified 37 additional SMYD5-regulated temperature-dependent genes, suggesting a broader MHR-related role for SMYD5. Our study provides an example of how histone modifications integrate environmental cues into the genetic circuitry of mammalian cells and provides insights that may yield therapeutic avenues for neuroprotection after catastrophic events.
轻度低温反应（MHR）在暴露于寒冷时维持机体的内稳态，被认为对治疗性低温所记录的神经保护至关重要。迄今为止，对于 MHR 的转录调控知之甚少。我们利用正向 CRISPR-Cas9 诱变筛选鉴定组蛋白赖氨酸甲基转移酶 SMYD5 作为 MHR 的调节剂。SMYD5 在体温下抑制关键的 MHR 基因 SP1。这种抑制与 SP1 基因座处组蛋白 H3 赖氨酸 26 三甲基化（H3K36me3）的温度依赖性水平相关，并且在全局范围内表明哺乳动物 MHR 受组蛋白修饰水平的调控。我们已经鉴定了 37 个额外的受 SMYD5 调节的温度依赖性基因，这表明 SMYD5 具有更广泛的与 MHR 相关的作用。我们的研究提供了一个例子，说明组蛋白修饰如何将环境线索整合到哺乳动物细胞的遗传电路中，并提供了可能为灾难性事件后神经保护产生治疗途径的见解。
