SMYD5 is a regulator of the mild hypothermia response

Salvor Rafnsdottir; Kijin Jang; Sara Tholl Halldorsdottir; Meghna Vinod; Arnhildur Tomasdottir; Katrin Möller; Katrin Halldorsdottir; Tinna Reynisdottir; Laufey Halla Atladottir; Kristin Elisabet Allison; Kevin Ostacolo; Jin He; Li Zhang; Frances J. Northington; Erna Magnusdottir; Raul Chavez-Valdez; Kimberley Jade Anderson; Hans Tomas Bjornsson

doi:10.1016/j.celrep.2024.114554

SMYD5 is a regulator of the mild hypothermia response

Salvor Rafnsdottir, Kijin Jang, Sara Tholl Halldorsdottir, Meghna Vinod, Arnhildur Tomasdottir, Katrin Möller, Katrin Halldorsdottir, Tinna Reynisdottir, Laufey Halla Atladottir, Kristin Elisabet Allison, Kevin Ostacolo, Jin He, Li Zhang, Frances J. Northington, Erna Magnusdottir, Raul Chavez-Valdez, Kimberley Jade Anderson, Hans Tomas Bjornsson

School of Medicine

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English (US)
Article number	114554
Journal	Cell Reports
Volume	43
Issue number	8
DOIs	https://doi.org/10.1016/j.celrep.2024.114554
State	Published - Aug 27 2024

Keywords

CP: Metabolism
H3K36me3
SP1
cold stress
epigenetics
genetic environmental interaction
histone machinery
histone methylation
hypoxic brain injury
proteasome
repressor

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2024.114554

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Rafnsdottir, S., Jang, K., Halldorsdottir, S. T., Vinod, M., Tomasdottir, A., Möller, K., Halldorsdottir, K., Reynisdottir, T., Atladottir, L. H., Allison, K. E., Ostacolo, K., He, J., Zhang, L., Northington, F. J., Magnusdottir, E., Chavez-Valdez, R., Anderson, K. J., & Bjornsson, H. T. (2024). SMYD5 is a regulator of the mild hypothermia response. Cell Reports, 43(8), Article 114554. https://doi.org/10.1016/j.celrep.2024.114554

Rafnsdottir, S, Jang, K, Halldorsdottir, ST, Vinod, M, Tomasdottir, A, Möller, K, Halldorsdottir, K, Reynisdottir, T, Atladottir, LH, Allison, KE, Ostacolo, K, He, J, Zhang, L, Northington, FJ, Magnusdottir, E, Chavez-Valdez, R, Anderson, KJ & Bjornsson, HT 2024, 'SMYD5 is a regulator of the mild hypothermia response', Cell Reports, vol. 43, no. 8, 114554. https://doi.org/10.1016/j.celrep.2024.114554

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abstract = "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.",

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AU - Rafnsdottir, Salvor

AU - Jang, Kijin

AU - Halldorsdottir, Sara Tholl

AU - Vinod, Meghna

AU - Tomasdottir, Arnhildur

AU - Möller, Katrin

AU - Halldorsdottir, Katrin

AU - Reynisdottir, Tinna

AU - Atladottir, Laufey Halla

AU - Allison, Kristin Elisabet

AU - Ostacolo, Kevin

AU - He, Jin

AU - Zhang, Li

AU - Northington, Frances J.

AU - Magnusdottir, Erna

AU - Chavez-Valdez, Raul

AU - Anderson, Kimberley Jade

AU - Bjornsson, Hans Tomas

PY - 2024/8/27

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N2 - 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.

AB - 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.

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KW - H3K36me3

KW - SP1

KW - cold stress

KW - epigenetics

KW - genetic environmental interaction

KW - histone machinery

KW - histone methylation

KW - hypoxic brain injury

KW - proteasome

KW - repressor

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JO - Cell Reports

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SMYD5 is a regulator of the mild hypothermia response

Abstract

Keywords

ASJC Scopus subject areas

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