Rafnsdottir Salvor, Jang Kijin, Halldorsdottir Sara Tholl, Vinod Meghna, Tomasdottir Arnhildur, Möller Katrin, Halldorsdottir Katrin, Reynisdottir Tinna, Atladottir Laufey Halla, Allison Kristin Elisabet, Ostacolo Kevin, He Jin, Zhang Li, Northington Frances J, Magnusdottir Erna, Chavez-Valdez Raul, Anderson Kimberley Jade, Bjornsson Hans Tomas
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.
bioRxiv. 2024 Jul 12:2023.05.11.540170. doi: 10.1101/2023.05.11.540170.
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 at euthermia. This repression correlates with temperature-dependent levels of H3K36me3 at the -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）在冷暴露期间维持机体稳态，并且被认为对于治疗性低温所记录的神经保护作用至关重要。迄今为止，对于MHR的转录调控知之甚少。我们利用正向CRISPR-Cas9诱变筛选来鉴定组蛋白赖氨酸甲基转移酶SMYD5作为MHR的调节因子。SMYD5在正常体温时抑制关键的MHR基因。这种抑制与该基因座以及整体上H3K36me3的温度依赖性水平相关，表明哺乳动物的MHR在组蛋白修饰水平上受到调控。我们还鉴定出另外37个受SMYD5调控的温度依赖性基因，提示SMYD5在与MHR相关方面具有更广泛的作用。我们的研究提供了一个组蛋白修饰如何将环境线索整合到哺乳动物细胞遗传回路中的例子，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。
