TY - JOUR
T1 - Long-term behavioral and cell-type-specific molecular effects of early life stress are mediated by H3K79me2 dynamics in medium spiny neurons
AU - Kronman, Hope
AU - Torres-Berrío, Angélica
AU - Sidoli, Simone
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.
N1 - Funding Information:
This work was supported by funding from the National Institutes of Health (P50 MH096890 and R01 MH051399 to E.J.N.) and the Hope for Depression Research Foundation. We also acknowledge R00MH115096 (to C.J.P.), K99DA042100 (to D.M.W.), NARSAD no. 26329 (to O.I.), an Umberto Mortari Award from Merck (to S.S.), grants from the Japan Agency for Medical Research and Development (to A.M.E.D.) and the New York Academy of Sciences (to S.S.).
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
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.
UR - http://www.scopus.com/inward/record.url?scp=85102581724&partnerID=8YFLogxK
U2 - 10.1038/s41593-021-00814-8
DO - 10.1038/s41593-021-00814-8
M3 - Article
C2 - 33723435
AN - SCOPUS:85102581724
SN - 1097-6256
VL - 24
SP - 667
EP - 676
JO - Nature neuroscience
JF - Nature neuroscience
IS - 5
ER -