Rafnsdottir, SalvorJang, KijinHalldorsdottir, Sara ThollVinod, MeghnaTomasdottir, ArnhildurMöller, KatrínHalldórsdóttir, KatrínReynisdóttir, TinnaAtladottir, Laufey HallaAllison, Kristín ElísabetOstacolo, Kévin Jean AntonioHe, JinZhang, LiNorthington, Frances J.Magnúsdóttir, ErnaChavez-Valdez, RaulAnderson, Kimberley JadeBjörnsson, Hans Tómas2025-11-202025-11-202024-08-27Rafnsdottir, S, Jang, K, Halldorsdottir, S T, Vinod, M, Tomasdottir, A, Möller, K, Halldórsdóttir, K, Reynisdóttir, T, Atladottir, L H, Allison, K E, Ostacolo, K J A, He, J, Zhang, L, Northington, F J, Magnúsdóttir, E, Chavez-Valdez, R, Anderson, K J & Björnsson, H T 2024, 'SMYD5 is a regulator of the mild hypothermia response', Cell Reports, vol. 43, no. 8, 114554. https://doi.org/10.1016/j.celrep.2024.1145542211-1247227694343dee98923-1327-48b7-b07a-2a415ea36bdf8519986801239083378https://hdl.handle.net/20.500.11815/7578Publisher Copyright: © 2024 The Author(s)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.6275462eninfo:eu-repo/semantics/openAccesscold stressCP: Metabolismepigeneticsgenetic environmental interactionH3K36me3histone machineryhistone methylationhypoxic brain injuryproteasomerepressorSP1Hypothermia/metabolismHumansGene Expression RegulationHistones/metabolismCRISPR-Cas Systems/geneticsAnimalsHistone-Lysine N-Methyltransferase/metabolismHEK293 CellsMiceMethylationGeneral Biochemistry,Genetics and Molecular Biology/dk/atira/pure/researchoutput/researchoutputtypes/contributiontojournal/article10.1016/j.celrep.2024.114554