title: Genome-wide alterations in hippocampal 5-hydroxymethylcytosine links plasticity genes to acute stress.
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.
authors.affiliation: Department of Psychiatry University of Wisconsin, Madison, WI, USA; Neuroscience Training Program, University of Wisconsin, Madison, WI, USA.
authors.forename: Sisi
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Psychiatry University of Wisconsin, Madison, WI, USA.
authors.forename: Ligia A
authors.initials: LA
authors.lastname: Papale
authors.affiliation: Department Statistics, Biostatistics, and Medical Informatics, University of Wisconsin, Madison, WI, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Psychiatry University of Wisconsin, Madison, WI, USA; Endocrinology and Reproductive Physiology Training Program, University of Wisconsin, Madison, WI, USA.
authors.forename: Andy
authors.initials: A
authors.lastname: Madrid
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Chopra
authors.affiliation: Department Statistics, Biostatistics, and Medical Informatics, University of Wisconsin, Madison, WI, USA.
authors.forename: Sündüz
authors.initials: S
authors.lastname: Keleş
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Jin
authors.affiliation: Department of Psychiatry University of Wisconsin, Madison, WI, USA. Electronic address: alisch@wisc.edu.
authors.forename: Reid S
authors.initials: RS
authors.lastname: Alisch
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives; D000818:Animals; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015870:Gene Expression; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity; D013315:Stress, Psychological / Q000235:genetics* / Q000378:metabolism*
chemical_list: C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine
keywords: 5-Hydroxymethylcytosine; Acute stress; DNA methylation; Epigenetics; Gene expression