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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

Nature Neuroscience volume 24, pages 667–676 (2021)Cite this article

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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.

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Fig. 1: Histone modifications after ELS point to persistent epigenetic changes.
Fig. 2: ELS alters the expression of Dot1l and Kdm2b over development, most intensely in D2 MSNs of males.
Fig. 3: D2 MSN-specific manipulation of Dot1l or Kdm2b alters ELS-induced behavior.
Fig. 4: D2 MSN-specific overexpression of Dot1l mimics ELS-induced transcription, whereas D2 MSN-specific Dot1l knockdown reverses ELS-induced transcription.
Fig. 5: H3K79me2 genome-wide pattern after ELS resembles ‘ELS-like’ transcription in D2 MSNs more than ‘Std-like’ transcription.
Fig. 6: Intraperitoneal pinometostat administration during CSDS reverses ELS-induced social interaction deficit.

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Data availability

RNA-seq and ChIP-seq datasets that supported this study (Figs. 4 and 5) have been deposited publicly in the Gene Expression Omnibus under accession code GSE133889. Detailed information on reporting can be found in the linked document titled ‘Life Sciences Reporting Summaryʼ. Source data are provided with this paper.

Code availability

All code used in this work for RNA-seq and ChIP-seq analyses is openly available and can be accessed through the following GitHub repositories, as well as in the file titled ‘Supplementary Software’.

ChIP-seq and RNA-seq raw data processing: https://github.com/shenlab-sinai/NGS-Data-Charmer

ChIP-seq differential analysis: https://github.com/shenlab-sinai/diffreps. Source data are provided with this paper.

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Acknowledgements

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.).

Author information

Author notes

  1. Casey K. Lardner

    Present address: Sackler Institute for Developmental Psychobiology, New York State Psychiatric Institute, and Departments of Pediatrics and Psychiatry, Columbia University, New York NY, USA

  2. Deena M. Walker

    Present address: Department of Neurobiology and Behavior, Oregon Health & Science University, Portland, OR, USA

  3. Catherine J. Peña

    Present address: Princeton Neuroscience Institute, Princeton University, Princeton, NJ, USA

  4. Simone Sidoli

    Present address: Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA

Authors and Affiliations

  1. Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Hope Kronman, Angélica Torres-Berrío, 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, Li Shen, Catherine J. Peña & Eric J. Nestler

  2. Department of Biochemistry and Biophysics and Epigenetics Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

    Simone Sidoli & Benjamin A. Garcia

  3. Department of Neurology, Massachusetts General Hospital, Boston, MA, USA

    Rachael Neve

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Contributions

H.K., C.J.P., A.T.B., P.M. and E.J.N. designed the studies. C.J.B. and A.T.B. built reversal learning equipment. H.K. and A.T.B. performed all behavioral experiments. With input from B.A.G., S.S. performed mass spectrometry on nuclei isolated by H.K. O.I. and H.K. cloned viral vectors, and R.N. packaged those vectors into viruses. A.G. assisted H.K. with western blotting, E.M.P. assisted H.K. with RNA in situ hybridization and B.B. helped optimize pinometostat administration by running pilot experiments with a separate cohort. H.K. generated all sequencing libraries and performed all qPCRs. C.K.L., Y.V.D.Z. and D.M.W. helped H.K. with stereotactic surgeries and animal sacrifices. A.R., with input from L.S., performed the processing of raw sequencing data as well as the genomic mapping of ChIP-seq data. H.K. performed all downstream data analysis. H.K. wrote the manuscript and prepared all of the figures. All authors discussed the results and edited and approved the manuscript.

Corresponding authors

Correspondence to Catherine J. Peña or Eric J. Nestler.

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The authors declare no competing financial interests.

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Peer review information Nature Neuroscience thanks Jeremy Day and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Mass spectrometry data principal components and networks of correlated marks.

(a) Principal component graphs; concentration ellipses determined by means and covariance of groups. Panel A shows PC1/PC2 and Panel B shows PC3/PC4 (b) Correlation by Euclidean distance of histone modifications within group (c) Fold change of epigenetic writers and erasers in male and female post-ELS NAc datasets from Peña et al30.

Extended Data Fig. 2 Viral validation and behavioral specificity.

(a) qPCR of Dot1l in whole NAc tissue following Dot1l knockdown using a cell-type-specific HSV. Significance by two-sided t-test (p=0.02), n=12 individual animals, error bars represent SEM. (b) qPCR of Dot1l in whole NAc tissue following Dot1l overexpression using a cell type-specific HSV. Significance by two-sided t-test (p=0.03), n=13 individual animals, error bars represent SEM. (c) qPCR of Kdm2b in whole NAc tissue following Kdm2b knockdown using a cell type-specific HSV. Significance by two-sided t-test (p=0.01), n=12 individual animals, error bars represent SEM. (d) qPCR of Kdm2b in whole NAc tissue following Kdm2b overexpression using a cell type-specific HSV. Significance by two-sided t-test (p=0.003), n=18 individual animals, error bars represent SEM. (e) Dot1l knockdown in D1 MSNs of male and female mice does not produce social interaction deficits following social defeat. Significance by 2-way ANOVA (n.s.), n=20 individual male animals and 20 individual female animals, error bars represent SEM. (f) Dot1l overexpression in D2 MSNs of the PFC does not produce social interaction deficits following social defeat. Significance by two-sided t-test (n.s.), n=14 individual animals, error bars represent SEM. (g) Snca overexpression in D2 MSNs of the NAc does not produce social interaction deficits following social defeat. Significance by two-sided t-test (n.s.), n=14 individual animals, error bars represent SEM. (h) Social interaction deficits are amplified over the week following social defeat. Significance by two-way ANOVA, n=22 individual animals, error bars represent SEM, lines represent Bonferroni post-test, ** < 0.001, *** < 0.0001.. (i) Std, ELS, and animals with D2 MSN-specific Dot1l overexpression all acquire the initial task with equal accuracy. Significance by two-sided t-test (n.s.), n=29 individual animals, error bars represent SEM. (j) qPCRs of whole NAc tissue from female ELS mice that underwent behavioral testing in Fig. 3. Significance by two-way ANOVA, n=20 individual animals, error bars represent SEM, with lines representing Bonferroni post-test, * < 0.05, ** < 0.001. (k) Correlation of male qPCRs with male behaviors from Figs. 4 and 3, respectively.

Extended Data Fig. 3 Whole tissue detection of H3K79me2 after D2 MSN-specific overexpression of Dot1l.

Performed by ELISA. Significance by two-sided t-test (p=0.03), n=10 individual animals, error bars represent SEM.

Extended Data Fig. 4 ChIP antibody, data quality, and baseline characteristics of H3K79me2 in NAc.

(a) DNA pulled down by IgG and H3K79me2 antibodies. Values represent percent of input (n=2 total samples, each with 2 pooled animals) (b) Distribution of H3K79me2 peaks in Std adult animals (c) Fold enrichment of H3K79me2 peaks in Std adult animals compared to gene length and transcript expression (baseMean value in ELS vs Std DESeq2 comparison). Pearson correlation shows r=-0.15, p<0.00001 (upper panel) and r=-0.01, n.s. (lower panel) (d) Percentage of H3K79me2 peaks in Std adult animals that overlap with enhancer loci predicted in mouse NAc. No enrichment of these enhancer-overlapping peaks.

Extended Data Fig. 5 Pinometostat treatment does not alter locomotor activity or weight.

(a) Schematic of IP Pinometostat administration (b) Locomotor activity after treatment with Pinometostat or saline. Measured in beam breaks. (c) Weight of Pinometostat- and saline-treated animals.

Extended Data Fig. 6 Representative gating for nuclear FACS.

(a) First gate on FSC-A vs SSC-A retrieves nuclei (circled) as opposed to debris (b) Second gate on FSC-A vs Blue1-A (FITC channel) separates transgenically labeled nuclei from wild-type nuclei.

Supplementary information

Reporting Summary

Supplementary Tables

Worksheet containing Supplementary Tables 1–4 in individual sheets

Source data

Source Data Fig. 2

DOT1L and ACTB full blots, separate stainings, Fig 2b.

Source Data Fig. 6

H3K79me2 and total H3 full blots, separate stainings, Fig 6a.

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Kronman, H., Torres-Berrío, A., Sidoli, S. et al. Long-term behavioral and cell-type-specific molecular effects of early life stress are mediated by H3K79me2 dynamics in medium spiny neurons. Nat Neurosci 24, 667–676 (2021). https://doi.org/10.1038/s41593-021-00814-8

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