title: Early-life stress links 5-hydroxymethylcytosine to anxiety-related behaviors.
abstract: Environmental stress contributes to the development of psychiatric disorders, including posttraumatic stress disorder and anxiety. 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 the brain and is associated with active transcription of neuronal genes. Here we examined behavioral and molecular alterations in adult mice that experienced an early-life stress before weaning (postnatal day 12 to 18) and found anxiety-like behaviors in adult female mice that were accompanied by correlated disruptions of hypothalamic 5hmC and gene expression in 118 genes, revealing potentially functional 5hmC (i.e., gene regulation). These genes are known and potentially novel stress-related targets, including Nr3c2, Nrxn1, Nfia, and Clip1, that have a significant enrichment for neuronal ontological functions, such as neuronal development and differentiation. Sequence motif predictions indicated that 5hmC may regulate gene expression by mediating transcription factor binding and alternative splicing of many of these transcripts. Together, these findings represent a critical step toward understanding the effects of early environment on the neuromolecular mechanisms that underlie the risk to develop anxiety disorders.
authors.affiliation: a Department of Psychiatry , University of Wisconsin , Madison , WI , USA.
authors.forename: Ligia A
authors.initials: LA
authors.lastname: Papale
authors.affiliation: a Department of Psychiatry , University of Wisconsin , Madison , WI , USA.|b Neuroscience Training Program , University of Wisconsin , Madison , WI , USA.
authors.forename: Andy
authors.initials: A
authors.lastname: Madrid
authors.affiliation: a Department of Psychiatry , University of Wisconsin , Madison , WI , USA.|b Neuroscience Training Program , University of Wisconsin , Madison , WI , USA.
authors.forename: Sisi
authors.initials: S
authors.lastname: Li
authors.affiliation: a Department of Psychiatry , University of Wisconsin , Madison , WI , USA.
authors.forename: Reid S
authors.initials: RS
authors.lastname: Alisch
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D001007:Anxiety / Q000378:metabolism*; D005260:Female; D008297:Male; D051379:Mice; D013312:Stress, Physiological
chemical_list: C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine
keywords: 5-hydroxymethylcytosine; DNA methylation; anxiety; early-life stress; epigenetics; gene expression