Long-term behavioral and cell-type-specific molecular effects of early life stress are mediated by H3K79me2 dynamics in medium spiny neurons

Hope Kronman; Angélica Torres-Berrío; Simone Sidoli; Orna Issler; Arthur Godino; Aarthi Ramakrishnan; Philipp Mews; Casey K. Lardner; Eric M. Parise; Deena M. Walker; Yentl Y. van der Zee; Caleb J. Browne; Brittany F. Boyce; Rachael Neve; Benjamin A. Garcia; Li Shen; Catherine J. Peña; Eric J. Nestler

doi:10.1038/s41593-021-00814-8

Long-term behavioral and cell-type-specific molecular effects of early life stress are mediated by H3K79me2 dynamics in medium spiny neurons

Hope Kronman, Angélica Torres-Berrío, Simone Sidoli, Orna Issler, Arthur Godino, Aarthi Ramakrishnan, Philipp Mews, Casey K. Lardner, Eric M. Parise, Deena M. Walker, Yentl Y. van der Zee, Caleb J. Browne, Brittany F. Boyce, Rachael Neve, Benjamin A. Garcia, Li Shen, Catherine J. Peña, Eric J. Nestler

Biochemistry

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

47 Scopus citations

Abstract

Animals susceptible to chronic social defeat stress (CSDS) exhibit depression-related behaviors, with aberrant transcription across several limbic brain regions, most notably in the nucleus accumbens (NAc). Early life stress (ELS) promotes susceptibility to CSDS in adulthood, but associated enduring changes in transcriptional control mechanisms in the NAc have not yet been investigated. In this study, we examined long-lasting changes to histone modifications in the NAc of male and female mice exposed to ELS. Dimethylation of lysine 79 of histone H3 (H3K79me2) and the enzymes (DOT1L and KDM2B) that control this modification are enriched in D2-type medium spiny neurons and are shown to be crucial for the expression of ELS-induced stress susceptibility. We mapped the site-specific regulation of this histone mark genome wide to reveal the transcriptional networks it modulates. Finally, systemic delivery of a small molecule inhibitor of DOT1L reversed ELS-induced behavioral deficits, indicating the clinical relevance of this epigenetic mechanism.

Original language	English (US)
Pages (from-to)	667-676
Number of pages	10
Journal	Nature Neuroscience
Volume	24
Issue number	5
DOIs	https://doi.org/10.1038/s41593-021-00814-8
State	Published - May 2021

ASJC Scopus subject areas

General Neuroscience

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10.1038/s41593-021-00814-8

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Kronman, H., Torres-Berrío, A., Sidoli, S., Issler, O., Godino, A., Ramakrishnan, A., Mews, P., Lardner, C. K., Parise, E. M., Walker, D. M., van der Zee, Y. Y., Browne, C. J., Boyce, B. F., Neve, R., Garcia, B. A., Shen, L., Peña, C. J., & Nestler, E. J. (2021). Long-term behavioral and cell-type-specific molecular effects of early life stress are mediated by H3K79me2 dynamics in medium spiny neurons. Nature Neuroscience, 24(5), 667-676. https://doi.org/10.1038/s41593-021-00814-8

Kronman, H, Torres-Berrío, A, Sidoli, S, Issler, O, Godino, A, Ramakrishnan, A, Mews, P, Lardner, CK, Parise, EM, Walker, DM, van der Zee, YY, Browne, CJ, Boyce, BF, Neve, R, Garcia, BA, Shen, L, Peña, CJ & Nestler, EJ 2021, 'Long-term behavioral and cell-type-specific molecular effects of early life stress are mediated by H3K79me2 dynamics in medium spiny neurons', Nature Neuroscience, vol. 24, no. 5, pp. 667-676. https://doi.org/10.1038/s41593-021-00814-8

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title = "Long-term behavioral and cell-type-specific molecular effects of early life stress are mediated by H3K79me2 dynamics in medium spiny neurons",

abstract = "Animals susceptible to chronic social defeat stress (CSDS) exhibit depression-related behaviors, with aberrant transcription across several limbic brain regions, most notably in the nucleus accumbens (NAc). Early life stress (ELS) promotes susceptibility to CSDS in adulthood, but associated enduring changes in transcriptional control mechanisms in the NAc have not yet been investigated. In this study, we examined long-lasting changes to histone modifications in the NAc of male and female mice exposed to ELS. Dimethylation of lysine 79 of histone H3 (H3K79me2) and the enzymes (DOT1L and KDM2B) that control this modification are enriched in D2-type medium spiny neurons and are shown to be crucial for the expression of ELS-induced stress susceptibility. We mapped the site-specific regulation of this histone mark genome wide to reveal the transcriptional networks it modulates. Finally, systemic delivery of a small molecule inhibitor of DOT1L reversed ELS-induced behavioral deficits, indicating the clinical relevance of this epigenetic mechanism.",

author = "Hope Kronman and Ang{\'e}lica Torres-Berr{\'i}o and Simone Sidoli and Orna Issler and Arthur Godino and Aarthi Ramakrishnan and Philipp Mews and Lardner, {Casey K.} and Parise, {Eric M.} and Walker, {Deena M.} and {van der Zee}, {Yentl Y.} and Browne, {Caleb J.} and Boyce, {Brittany F.} and Rachael Neve and Garcia, {Benjamin A.} and Li Shen and Pe{\~n}a, {Catherine J.} and Nestler, {Eric J.}",

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year = "2021",

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doi = "10.1038/s41593-021-00814-8",

language = "English (US)",

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AU - Torres-Berrío, Angélica

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AU - Issler, Orna

AU - Godino, Arthur

AU - Ramakrishnan, Aarthi

AU - Mews, Philipp

AU - Lardner, Casey K.

AU - Parise, Eric M.

AU - Walker, Deena M.

AU - van der Zee, Yentl Y.

AU - Browne, Caleb J.

AU - Boyce, Brittany F.

AU - Neve, Rachael

AU - Garcia, Benjamin A.

AU - Shen, Li

AU - Peña, Catherine J.

AU - Nestler, Eric J.

PY - 2021/5

Y1 - 2021/5

N2 - Animals susceptible to chronic social defeat stress (CSDS) exhibit depression-related behaviors, with aberrant transcription across several limbic brain regions, most notably in the nucleus accumbens (NAc). Early life stress (ELS) promotes susceptibility to CSDS in adulthood, but associated enduring changes in transcriptional control mechanisms in the NAc have not yet been investigated. In this study, we examined long-lasting changes to histone modifications in the NAc of male and female mice exposed to ELS. Dimethylation of lysine 79 of histone H3 (H3K79me2) and the enzymes (DOT1L and KDM2B) that control this modification are enriched in D2-type medium spiny neurons and are shown to be crucial for the expression of ELS-induced stress susceptibility. We mapped the site-specific regulation of this histone mark genome wide to reveal the transcriptional networks it modulates. Finally, systemic delivery of a small molecule inhibitor of DOT1L reversed ELS-induced behavioral deficits, indicating the clinical relevance of this epigenetic mechanism.

AB - Animals susceptible to chronic social defeat stress (CSDS) exhibit depression-related behaviors, with aberrant transcription across several limbic brain regions, most notably in the nucleus accumbens (NAc). Early life stress (ELS) promotes susceptibility to CSDS in adulthood, but associated enduring changes in transcriptional control mechanisms in the NAc have not yet been investigated. In this study, we examined long-lasting changes to histone modifications in the NAc of male and female mice exposed to ELS. Dimethylation of lysine 79 of histone H3 (H3K79me2) and the enzymes (DOT1L and KDM2B) that control this modification are enriched in D2-type medium spiny neurons and are shown to be crucial for the expression of ELS-induced stress susceptibility. We mapped the site-specific regulation of this histone mark genome wide to reveal the transcriptional networks it modulates. Finally, systemic delivery of a small molecule inhibitor of DOT1L reversed ELS-induced behavioral deficits, indicating the clinical relevance of this epigenetic mechanism.

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Long-term behavioral and cell-type-specific molecular effects of early life stress are mediated by H3K79me2 dynamics in medium spiny neurons

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