Low levels of Methyl-CpG binding protein 2 are accompanied by an increased vulnerability to the negative outcomes of stress exposure during childhood in healthy women

Abstract

Numerous mental illnesses arise following stressful events in vulnerable individuals, with females being generally more affected than males. Adverse childhood experiences are known to increase the risk of developing psychopathologies and DNA methylation was demonstrated to drive the long-lasting effects of early life stress and promote stress susceptibility. Methyl-CpG binding protein 2 (MECP2), an X-linked reader of the DNA methylome, is altered in many mental disorders of stress origin, suggesting MECP2 as a marker of stress susceptibility; previous works also suggest a link between MECP2 and early stress experiences. The present work explored whether a reduced expression of MECP2 is paralleled by an increased vulnerability to the negative outcomes of stress exposure during childhood. To this aim, blood MECP2 mRNA levels were analyzed in 63 people without history of mental disorders and traits pertaining to depressive and anxiety symptom clusters were assessed as proxies of the vulnerability to develop stress-related disorders; stress exposure during childhood was also evaluated. Using structural equation modeling, we demonstrate that reduced MECP2 expression is accompanied by symptoms of anxiety/depression in association with exposure to stress in early life, selectively in healthy women. These results suggest a gender-specific involvement of MECP2 in the maladaptive outcomes of childhood adversities, and shed new light on the complex biology underlying gender bias in stress susceptibility.

Contribution of changes in the orexin system and energy sensors in the brain in depressive disorder - a study in an animal model

“…MeCP2 binds methylated CpG dinucleotides and forms a complex with histone deacetylase, which triggers chromatin structure remodeling by histone deacetylation and represses transcription. MeCP2 is downregulated in many stress-induced psychiatric disorders and is thought to be a marker of vulnerability to stress, and a link between MeCP2 and early stress experiences has been suggested [ 50 ]. Among other things, it has been shown that the binding of MeCP2 and Dnmt1 to the promoter of the gene encoding reelin leads to the inhibition of the synthesis of this protein, which is important in the process of neuronal migration during the developmental period and synaptic plasticity and neurogenesis in the adult brain [ 51 , 52 ].…”

Evidence Synthesis of Gene Therapy and Gene Editing from Different Disorders—Implications for Individuals with Rett Syndrome: A Systematic Review

“…Newborn screening for RTT would also need to consider the alterations of the MECP2 gene within the healthy population. Reduced gene expression can increase the vulnerability to stress in healthy females [7], and variations in healthy control populations have also been described [90]. Any newborn screening strategy will need to have a threshold at which MECP2 becomes pathogenic.…”

“…Looking more broadly, it is likely that MECP2 has modulatory effects across the genome. Indeed, stress during early life epochs is associated with anxiety and depression, concomitantly reducing MeCP2 expression in healthy females [7]. This finding suggests that the MECP2 gene has genome-wide influences and that the MeCP2 protein significantly modulates vulnerability to psychopathology.…”

Methyl-CpG binding protein 2 expression is associated with symptom severity in patients with PTSD in a sex-dependent manner

“…Whole blood was collected in PAXgene Blood RNA Tubes (PreAnalytiX, Hombrechtikon Switzerland) and stored until analysis at −80 °C [ 43 , 55 ]. A PAXgene Blood miRNA Kit (Qiagen, Hilden, Germany) was used to extract total RNA, following the manufacturer´s instructions.…”

“…Interestingly, a sex-specific modulation of MECP2 expression has previously been described in rodents following stress exposure early in life [ 41 , 42 ]. Furthermore, in a non-clinical population sample we recently demonstrated that reduced levels of MECP2 are linked to an increased risk of psychopathology following childhood adversities selectively in women [ 43 ]. Given that early-life adversities, vulnerability to psychopathology and female sex are factors known to intensify the impact of exposure to traumatic experiences in adulthood, eventually increasing the risk of PTSD onset [ 44 , 45 ], these findings confirm the need of further exploring the role of MECP2 in the pathogenesis of PTSD.…”