Unbiased Screening Identifies Functional Differences in NK Cells After Early Life Psychosocial Stress.

Early Life Adversity (ELA) is closely associated with the risk for developing diseases later in life, such as autoimmune diseases, type-2 diabetes and cardiovascular diseases. In humans, early parental separation, physical and sexual abuse or low social-economic status during childhood are known to have great impact on brain development, in the hormonal system and immune responses. Maternal deprivation (MD) is the closest animal model available to the human situation. This paradigm induces long lasting behavioral effects, causes changes in the HPA axis and affects the immune system. However, the mechanisms underlying changes in the immune response after ELA are still not fully understood. In this study we investigated how ELA changes the immune system, through an unbiased analysis, viSNE, and addressed specially the NK immune cell population and its functionality. We have demonstrated that maternal separation, in both humans and rats, significantly affects the sensitivity of the immune system in adulthood. Particularly, NK cells' profile and response to target cell lines are significantly changed after ELA. These immune cells in rats are not only less cytotoxic towards YAC-1 cells, but also show a clear increase in the expression of maturation markers after 3h of maternal separation. Similarly, individuals who suffered from ELA display significant changes in the cytotoxic profile of NK cells together with decreased degranulation capacity. These results suggest that one of the key mechanisms by which the immune system becomes impaired after ELA might be due to a shift on the senescent state of the cells, specifically NK cells. Elucidation of such a mechanism highlights the importance of ELA prevention and how NK targeted immunotherapy might help attenuating ELA consequences.

N6-Methyladenine in Eukaryotic DNA: Tissue Distribution, Early Embryo Development, and Neuronal Toxicity.

DNA methylation is one of the most important epigenetic modifications and is closely related with several biological processes such as regulation of gene transcription and the development of non-malignant diseases. The prevailing dogma states that DNA methylation in eukaryotes occurs essentially through 5-methylcytosine (5mC) but recently adenine methylation was also found to be present in eukaryotes. In mouse embryonic stem cells, 6-methyladenine (6mA) was associated with the repression and silencing of genes, particularly in the X-chromosome, known to play an important role in cell fate determination. Here, we have demonstrated that 6mA is a ubiquitous eukaryotic epigenetic modification that is put in place during epigenetically sensitive periods such as embryogenesis and fetal development. In somatic cells there are clear tissue specificity in 6mA levels, with the highest 6mA levels being observed in the brain. In zebrafish, during the first 120 h of embryo development, from a single pluripotent cell to an almost fully formed individual, 6mA levels steadily increase. An identical pattern was observed over embryonic days 7-21 in the mouse. Furthermore, exposure to a neurotoxic environmental pollutant during the same early life period may led to a decrease in the levels of this modification in female rats. The identification of the periods during which 6mA epigenetic marks are put in place increases our understanding of this mammalian epigenetic modification, and raises the possibility that it may be associated with developmental processes.