The evolutionarily conserved miRNA-137 targets the neuropeptide hypocretin/orexin and modulates the wake to sleep ratio

Anja Holm; Marie Laure Possovre; Mojtaba Bandarabadi; Kristine F. Moseholm; Jessica L. Justinussen; Ivan Bozic; René Lemcke; Yoan Arribat; Francesca Amati; Asli Silahtaroglu; Maxime Juventin; Antoine Adamantidis; Mehdi Tafti; Birgitte R. Kornum

doi:10.1073/pnas.2112225119

The evolutionarily conserved miRNA-137 targets the neuropeptide hypocretin/orexin and modulates the wake to sleep ratio

Anja Holm, Marie Laure Possovre, Mojtaba Bandarabadi, Kristine F. Moseholm, Jessica L. Justinussen, Ivan Bozic, René Lemcke, Yoan Arribat, Francesca Amati, Asli Silahtaroglu, Maxime Juventin, Antoine Adamantidis, Mehdi Tafti, Birgitte R. Kornum

Research output: Contribution to journal › Journal article › Research › peer-review

25 Citations (Scopus)

83 Downloads (Pure)

Abstract

SignificanceThe hypocretin (Hcrt, also known as orexin) neuropeptides regulate sleep and wake stability, and disturbances of Hcrt can lead to sleep disorders. MicroRNAs (miRNAs) are short noncoding RNAs that fine-tune protein expression levels, and miRNA-based therapeutics are emerging. We report a functional interaction between miRNA (miR-137) and Hcrt. We demonstrate that intracellular miR-137 levels in Hcrt neurons regulate Hcrt expression with downstream effects on wakefulness. Specifically, lowering of miR-137 levels increased wakefulness in mice. We further show that the miR-137:Hcrt interaction is conserved across mice and humans, that miR-137 also regulates sleep-wake balance in zebrafish, and that the MIR137 locus is genetically associated with sleep duration in humans. Together, our findings reveal an evolutionarily conserved sleep-wake regulatory role of miR-137.

Original language	English
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	119
Issue number	17
Number of pages	10
ISSN	0027-8424
DOIs	https://doi.org/10.1073/pnas.2112225119
Publication status	Published - 2022

Keywords

hypocretin
miR-137
orexin
sleep
wake

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Holm, A., Possovre, M. L., Bandarabadi, M., Moseholm, K. F., Justinussen, J. L., Bozic, I., Lemcke, R., Arribat, Y., Amati, F., Silahtaroglu, A., Juventin, M., Adamantidis, A., Tafti, M., & Kornum, B. R. (2022). The evolutionarily conserved miRNA-137 targets the neuropeptide hypocretin/orexin and modulates the wake to sleep ratio. Proceedings of the National Academy of Sciences of the United States of America, 119(17). https://doi.org/10.1073/pnas.2112225119

The evolutionarily conserved miRNA-137 targets the neuropeptide hypocretin/orexin and modulates the wake to sleep ratio. / Holm, Anja; Possovre, Marie Laure; Bandarabadi, Mojtaba et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 119, No. 17, 2022.

Research output: Contribution to journal › Journal article › Research › peer-review

Holm, A, Possovre, ML, Bandarabadi, M, Moseholm, KF , Justinussen, JL, Bozic, I, Lemcke, R, Arribat, Y, Amati, F, Silahtaroglu, A, Juventin, M, Adamantidis, A, Tafti, M & Kornum, BR 2022, 'The evolutionarily conserved miRNA-137 targets the neuropeptide hypocretin/orexin and modulates the wake to sleep ratio', Proceedings of the National Academy of Sciences of the United States of America, vol. 119, no. 17. https://doi.org/10.1073/pnas.2112225119

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abstract = "SignificanceThe hypocretin (Hcrt, also known as orexin) neuropeptides regulate sleep and wake stability, and disturbances of Hcrt can lead to sleep disorders. MicroRNAs (miRNAs) are short noncoding RNAs that fine-tune protein expression levels, and miRNA-based therapeutics are emerging. We report a functional interaction between miRNA (miR-137) and Hcrt. We demonstrate that intracellular miR-137 levels in Hcrt neurons regulate Hcrt expression with downstream effects on wakefulness. Specifically, lowering of miR-137 levels increased wakefulness in mice. We further show that the miR-137:Hcrt interaction is conserved across mice and humans, that miR-137 also regulates sleep-wake balance in zebrafish, and that the MIR137 locus is genetically associated with sleep duration in humans. Together, our findings reveal an evolutionarily conserved sleep-wake regulatory role of miR-137.",

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T1 - The evolutionarily conserved miRNA-137 targets the neuropeptide hypocretin/orexin and modulates the wake to sleep ratio

AU - Holm, Anja

AU - Possovre, Marie Laure

AU - Bandarabadi, Mojtaba

AU - Moseholm, Kristine F.

AU - Justinussen, Jessica L.

AU - Bozic, Ivan

AU - Lemcke, René

AU - Arribat, Yoan

AU - Amati, Francesca

AU - Silahtaroglu, Asli

AU - Juventin, Maxime

AU - Adamantidis, Antoine

AU - Tafti, Mehdi

AU - Kornum, Birgitte R.

PY - 2022

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N2 - SignificanceThe hypocretin (Hcrt, also known as orexin) neuropeptides regulate sleep and wake stability, and disturbances of Hcrt can lead to sleep disorders. MicroRNAs (miRNAs) are short noncoding RNAs that fine-tune protein expression levels, and miRNA-based therapeutics are emerging. We report a functional interaction between miRNA (miR-137) and Hcrt. We demonstrate that intracellular miR-137 levels in Hcrt neurons regulate Hcrt expression with downstream effects on wakefulness. Specifically, lowering of miR-137 levels increased wakefulness in mice. We further show that the miR-137:Hcrt interaction is conserved across mice and humans, that miR-137 also regulates sleep-wake balance in zebrafish, and that the MIR137 locus is genetically associated with sleep duration in humans. Together, our findings reveal an evolutionarily conserved sleep-wake regulatory role of miR-137.

AB - SignificanceThe hypocretin (Hcrt, also known as orexin) neuropeptides regulate sleep and wake stability, and disturbances of Hcrt can lead to sleep disorders. MicroRNAs (miRNAs) are short noncoding RNAs that fine-tune protein expression levels, and miRNA-based therapeutics are emerging. We report a functional interaction between miRNA (miR-137) and Hcrt. We demonstrate that intracellular miR-137 levels in Hcrt neurons regulate Hcrt expression with downstream effects on wakefulness. Specifically, lowering of miR-137 levels increased wakefulness in mice. We further show that the miR-137:Hcrt interaction is conserved across mice and humans, that miR-137 also regulates sleep-wake balance in zebrafish, and that the MIR137 locus is genetically associated with sleep duration in humans. Together, our findings reveal an evolutionarily conserved sleep-wake regulatory role of miR-137.

KW - hypocretin

KW - miR-137

KW - orexin

KW - sleep

KW - wake

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DO - 10.1073/pnas.2112225119

M3 - Journal article

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JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

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