title: Glucocorticoid receptor gene (NR3C1) methylation processes as mediators of early adversity in stress-related disorders causality: A critical review.
abstract: Early life stress (ELS) is a known risk factor for suffering psychopathology in adulthood. The hypothalamic-pituitary-adrenal (HPA) axis has been described to be deregulated in both individuals who experienced early psychosocial stress and in patients with a wide range of psychiatric disorders. The NR3C1 gene codes for the glucocorticoid receptor, a key element involved in several steps of HPA axis modulation. In this review, we gather existing evidence linking NR3C1 methylation pattern with either ELS or psychopathology. We summarize that several types of ELS have been frequently associated with NR3C1 hypermethylation whereas hypomethylation has been continuously found to be associated with post-traumatic stress disorder. In light of the reported findings, the main concerns of ongoing research in this field are the lack of methodological consensus and selection of CpG sites. Further studies should target individual CpG site methylation assessment focusing in biologically relevant areas such as transcription factor binding regions whereas widening the examined sequence in order to include all non-coding first exons of the NR3C1 gene in the analysis.
authors.affiliation: Unity of Anthropology, Departament of Animal Biology, Faculty of Biology, Instituto de Biomedicina (IBUB), Universidad de Barcelona (UB), Av. Diagonal, 643, 08028 Barcelona, Spain.
authors.forename: Helena
authors.initials: H
authors.lastname: Palma-Gudiel
authors.affiliation: Unity of Anthropology, Departament of Animal Biology, Faculty of Biology, Instituto de Biomedicina (IBUB), Universidad de Barcelona (UB), Av. Diagonal, 643, 08028 Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), C/ Doctor Esquerdo, 46, 28007 Madrid, Spain.
authors.forename: Aldo
authors.initials: A
authors.lastname: Córdova-Palomera
authors.affiliation: Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), C/ Doctor Esquerdo, 46, 28007 Madrid, Spain; Department of Pharmacology, Faculty of Medicine, Universidad Complutense, Madrid, Spain.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Leza
authors.affiliation: Unity of Anthropology, Departament of Animal Biology, Faculty of Biology, Instituto de Biomedicina (IBUB), Universidad de Barcelona (UB), Av. Diagonal, 643, 08028 Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), C/ Doctor Esquerdo, 46, 28007 Madrid, Spain. Electronic address: lfananas@ub.edu.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Fañanás
mesh_terms: D000818:Animals; D001483:Base Sequence; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D013313:Stress Disorders, Post-Traumatic / Q000235:genetics; D013315:Stress, Psychological / Q000235:genetics*; D000068099:Trauma and Stressor Related Disorders / Q000235:genetics*
chemical_list: C497713:NR3C1 protein, human; D011965:Receptors, Glucocorticoid
keywords: DNA methylation; Early life stress; Glucocorticoid receptor; NR3C1 gene; Stress-related disorders