title: Sex-specific hippocampal 5-hydroxymethylcytosine is disrupted in response to acute stress.
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.
authors: Department of Psychiatry, University of Wisconsin, Madison, WI, USA.
authors: Ligia A
authors: LA
authors: Papale
authors: Department of Psychiatry, University of Wisconsin, Madison, WI, USA; Neuroscience Training Program, University of Wisconsin, Madison, WI, USA.
authors: Sisi
authors: S
authors: Li
authors: Department of Psychiatry, University of Wisconsin, Madison, WI, USA; Neuroscience Training Program, University of Wisconsin, Madison, WI, USA.
authors: Andy
authors: A
authors: Madrid
authors: Department of Statistics, University of Nebraska, Lincoln, NE, USA.
authors: Qi
authors: Q
authors: Zhang
authors: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
authors: Li
authors: L
authors: Chen
authors: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
authors: Pankaj
authors: P
authors: Chopra
authors: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
authors: Peng
authors: P
authors: Jin
authors: Department of Statistics, Biostatistics, and Medical Informatics, University of Wisconsin, Madison, WI, USA.
authors: Sündüz
authors: S
authors: Keleş
authors: Department of Psychiatry, University of Wisconsin, Madison, WI, USA. Electronic address: alisch@wisc.edu.
authors: Reid S
authors: RS
authors: Alisch
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives* / Q000633:toxicity; D000818:Animals; D047369:Chromatin Immunoprecipitation; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic / Q000187:drug effects* / Q000235:genetics; D005260:Female; D063990:Gene Ontology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008745:Methylation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D012737:Sex Factors; D013315:Stress, Psychological / Q000139:chemically induced* / Q000473:pathology*
chemical_list: C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine
keywords: 5-Hydroxymethylcytosine; Acute stress; DNA methylation; Epigenetics; Gene expression; Sex-specific