MORC1 exhibits cross-species differential methylation in association with early life stress as well as genome-wide association with MDD

Abstract

Early life stress (ELS) is associated with increased vulnerability for diseases in later life, including psychiatric disorders. Animal models and human studies suggest that this effect is mediated by epigenetic mechanisms. In humans, epigenetic studies to investigate the influence of ELS on psychiatric phenotypes are limited by the inaccessibility of living brain tissue. Due to the tissue-specific nature of epigenetic signatures, it is impossible to determine whether ELS induced epigenetic changes in accessible peripheral cells, for example, blood lymphocytes, reflect epigenetic changes in the brain. To overcome these limitations, we applied a cross-species approach involving: (i) the analysis of CD34+ cells from human cord blood; (ii) the examination of blood-derived CD3+ T cells of newborn and adolescent nonhuman primates (Macaca mulatta); and (iii) the investigation of the prefrontal cortex of adult rats. Several regions in MORC1 (MORC family CW-type zinc finger 1; previously known as: microrchidia (mouse) homolog) were differentially methylated in response to ELS in CD34+ cells and CD3+ T cells derived from the blood of human and monkey neonates, as well as in CD3+ T cells derived from the blood of adolescent monkeys and in the prefrontal cortex of adult rats. MORC1 is thus the first identified epigenetic marker of ELS to be present in blood cell progenitors at birth and in the brain in adulthood. Interestingly, a gene-set-based analysis of data from a genome-wide association study of major depressive disorder (MDD) revealed an association of MORC1 with MDD.

Maternal psychosocial stress during pregnancy alters the epigenetic signature of the glucocorticoid receptor gene promoter in their offspring: a meta-analysis

“…On the contrary, these studies detected non-replicated significant hits in a number of genes such as MORC1, LTA, SGC5, TNFRSF21, CHRNA2, or COL7A1, among others. [55][56][57][58] Interestingly, antidepressant treatment during pregnancy seems to be a major influencing factor, which would be in line with the discussion above. In this regard, Non and colleagues reported several changes in methylation only in the non-medicated depressed group when compared to healthy controls.…”

Intergenerational Transmission of Stress in Humans

“…MORC1 (MORC family CW-type zinc-finger 1) promoter hypomethylation was observed in human, monkey, and rat offspring exposed to early-life stress. Although a gene-based case-control analysis demonstrated an association between MORC1 and depression, the specific role of MORC1 is largely unknown (Nieratschker et al, 2014). Furthermore, prenatal maternal objective hardship in response to the 1998 Quebec ice storm was associated with a DNA methylation changes specific to genes related to immune function in CD3+ T cells of offspring at~13 years of age (Cao-Lei et al, 2014).…”

Traumatic Stress and Human DNA Methylation: A Critical Review

“…Alternatively, a comparison of animal model brain to blood may allow an inference of cross tissue epigenetic agreement. In some cases, a comparison of human blood-based findings to animal model-related brain findings has led to useful discoveries in psychiatric phenotypes [78,79]. However, the relevance of the model to the psychiatric phenotype in question must be considered with care.…”