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Author Notes:

Correspondence to: Reid S. Alisch, Department of Psychiatry, University of Wisconsin School of Medicine, 6001 Research Park Blvd., Madison, WI 53719-1176, alisch@wisc.edu, Phone: (608) 262-8430

Ligia A. Papale and Sisi Li contributed equally to this work.

The authors would like to thank Kim Sorens, the WISPIC animal facility, and the UW biotechnology center.

The authors declare no competing financial interests.

Subjects:

Research Funding:

This work was supported in part by the University of Wisconsin-Madison department of Psychiatry, University of Wisconsin Vilas Cycle Professorships #133AAA2989 and University of Wisconsin Graduate School #MSN184352 (all to RSA), NARSAD Young Investigator Grant from the Brain & Behavioral Research Foundation #22669 (LP), National Science Foundation under Grant No. 1400815 (AM), University of Wisconsin Neuroscience training grant T32-GM007507 (SL) and NIH grants HG003747 and U54AI117924 (SK), HG007019 (SK and QZ).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Neurosciences
  • Neurosciences & Neurology
  • Sex-specific
  • Acute stress
  • Epigenetics
  • DNA methylation
  • 5-Hydroxymethylcytosine
  • Gene expression
  • MAJOR DEPRESSIVE DISORDER
  • OBSESSIVE-COMPULSIVE DISORDER
  • GENOME-WIDE ASSOCIATION
  • HUMAN BRAIN-TISSUE
  • BIPOLAR DISORDER
  • DNA METHYLATION
  • GENE-EXPRESSION
  • ALZHEIMERS-DISEASE
  • SCHIZOPHRENIA-PATIENTS
  • PARKINSONS-DISEASE

Sex-specific hippocampal 5-hydroxymethylcytosine is disrupted in response to acute stress

Tools:

Journal Title:

Neurobiology of Disease

Volume:

Volume 96

Publisher:

, Pages 54-66

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Environmental stress is among the most important contributors to increased susceptibility to develop psychiatric disorders. While it is well known that acute environmental stress alters gene expression, the molecular mechanisms underlying these changes remain largely unknown. 5-hydroxymethylcytosine (5hmC) is a novel environmentally sensitive epigenetic modification that is highly enriched in neurons and is associated with active neuronal transcription. Recently, we reported a genome-wide disruption of hippocampal 5hmC in male mice following acute stress that was correlated to altered transcript levels of genes in known stress related pathways. Since sex-specific endocrine mechanisms respond to environmental stimulus by altering the neuronal epigenome, we examined the genome-wide profile of hippocampal 5hmC in female mice following exposure to acute stress and identified 363 differentially hydroxymethylated regions (DhMRs) linked to known (e.g., Nr3c1 and Ntrk2) and potentially novel genes associated with stress response and psychiatric disorders. Integration of hippocampal expression data from the same female mice found stress-related hydroxymethylation correlated to altered transcript levels. Finally, characterization of stress-induced sex-specific 5hmC profiles in the hippocampus revealed 778 sex-specific acute stress-induced DhMRs some of which were correlated to altered transcript levels that produce sex-specific isoforms in response to stress. Together, the alterations in 5hmC presented here provide a possible molecular mechanism for the adaptive sex-specific response to stress that may augment the design of novel therapeutic agents that will have optimal effectiveness in each sex.

Copyright information:

© 2016 The Author(s)

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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