Genome-wide alterations in hippocampal 5-hydroxymethylcytosine links plasticity genes to acute stress

• Type of Material: Article
• Authors: Sisi Li, University of Wisconsin; Ligia A. Papale, University of Wisconsin; Qi Zhang, University of Wisconsin; Andy Madrid, University of Wisconsin; Li Chen, Emory University; Pankaj Chopra, Emory University; Sunduz Keles, University of Wisconsin; Peng Jin, Emory University; Reid S. Alisch, University of Wisconsin
• Language: English
• Date: 2016-02-01
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2015 Elsevier Inc. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1016/j.nbd.2015.11.010
• Title of Journal or Parent Work: Neurobiology of Disease
• ISSN: 0969-9961
• Volume: 86
• Start Page: 99
• End Page: 108
• Grant/Funding Information: This work was supported in part by the University of Wisconsin-Madison department of Psychiatry (RSA), the University of Wisconsin Neuroscience training grant T32-GM007507 (SL), NARSAD Young Investigator Grant from the Brain & Behavioral Research Foundation #22669 (LP).
• Keywords: Life Sciences & Biomedicine; Acute stress; Gene expression; DNA METHYLATION; PROMOTER HYPERMETHYLATION; ANXIOUS TEMPERAMENT; DNA methylation; BIPOLAR DISORDER; Neurosciences; Epigenetics; RNA-SEQ; Science & Technology; EXPRESSION ANALYSIS; AUTISM SPECTRUM DISORDER; 5-Hydroxymethylcytosine; Neurosciences & Neurology; CORTICOTROPIN-RELEASING-FACTOR; ALZHEIMERS-DISEASE; TRANSCRIPTION FACTOR
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

Environmental stress is among the most important contributors to increased susceptibility to develop psychiatric disorders, including anxiety and post-traumatic stress disorder. While even acute stress alters gene expression, the molecular mechanisms underlying these changes remain largely unknown. 5-hydroxymethylcytosine (5hmC) is a novel environmentally sensitive DNA modification that is highly enriched in post-mitotic neurons and is associated with active transcription of neuronal genes. Recently, we found a hippocampal increase of 5hmC in the glucocorticoid receptor gene (Nr3c1) following acute stress, warranting a deeper investigation of stress-related 5hmC levels. Here we used an established chemical labeling and affinity purification method coupled with high-throughput sequencing technology to generate the first genome-wide profile of hippocampal 5hmC following exposure to acute restraint stress and a one-hour recovery. This approach found a genome-wide disruption in 5hmC associated with acute stress response, primarily in genic regions, and identified known and potentially novel stress-related targets that have a significant enrichment for neuronal ontological functions. Integration of these data with hippocampal gene expression data from these same mice found stress-related hydroxymethylation correlated to altered transcript levels and sequence motif predictions indicated that 5hmC may function by mediating transcription factor binding to these transcripts. Together, these data reveal an environmental impact on this newly discovered epigenetic mark in the brain and represent a critical step toward understanding stress-related epigenetic mechanisms that alter gene expression and can lead to the development of psychiatric disorders.