Browsing by Subject "epigenetics"
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(2021)Epigenetics is the study of changes in gene function without affecting the DNA sequence. Epigenetics studies the effects of the environment and behavior on the genome. Researchers have been able to detect several epigenetic modifications such as –DNA methylation, histone acetylation, and microRNA-associated gene silencing. Changes in the epigenome are essential for proper cell function and normal development and can also be induced by environmental factors. Stress is defined as a biological response to physiological and psychological demands which can affect cellular homeostasis. Factors such as prenatal life stress can affect gene function without directly altering the DNA nucleotide sequence. Elevated levels of stress can immobilize with the ability to impair cognitive function. There is evidence that suggests the involvement of epigenetic regulation in disorders such as addiction, depression, schizophrenia, and cognitive dysfunction. Therefore, this systematic review discusses recent findings of the role of epigenetics in prenatal exposure to stress. To achieve this, the thesis will cover different subtopics from genetics, neurobiology, and diseases, neuroscience, biological psychiatry, life sciences, medicine, behavioral brain research, biochemistry & molecular biology, as well as neuroendocrinology. Research questions are 1) Is there an association between epigenetics and prenatal stress? 2) What kind of mechanisms have been found? 3) What kind of techniques have been used in the identification of potential epigenetic mechanisms? What genes are associated with these epigenetic changes?. This study followed the "The Preferred Reporting Items for Systematic Reviews and Meta-Analyses" (PRISMA) guideline checklist. Eligibility criteria and search terms where be selected and documented to offer the widest range of articles covering the subjects of this study. A literature search was done using PubMed/Medline, Google scholar, and gray literature. The last sample comprised 59 articles. Data were extracted so that the participants, intervention, comparisons, and outcomes were included. The literature search conducted in this systematic review identified a few findings. First is that the majority of animal and human studies found a significant or moderate association between epigenetics and prenatal stress. Second, DNA methylation is the most studied epigenetic mechanism in maternal exposure to stress Third, genome-wide studies were more common in human studies than in animals and the most widely used method used is Infinium HumanMethylation450 Bead Chip. However, the common methods used in human and animal studies are most likely because of the small sample size and causation cannot be determined. Finally, NR3C1 and FKBP5 genes were the most studied in human studies where they showed the strongest association between prenatal stress and epigenetic modifications. While in animal studies, the most studied genes were Bdnf and Dnmt1 as they showed a significant methylation level after maternal prenatal stress exposure. In conclusion, maternal prenatal stress could trigger epigenetic alterations in neonates in both animals and humans. This holistic review detailed and evaluated locus-specific and studies exploring current knowledge about associations between maternal prenatal stress and epigenetic changes.
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(2021)Long non-coding RNAs (lncRNAs) are over 200 bp long RNA molecules that are not translated into protein. LncRNAs can regulate the expression of protein coding genes, and studies have indicated their role in stress response. Stress response has also been associated with differences in the structure of the myelin sheaths in the mouse brain cortex. Myelin is produced by mature oligodendrocytes (OLGs), and therefore, OLGs are likely to play a role in stress response. The aim of this thesis was to find lncRNAs differentially expressed in the oligodendrocytes and myelin on the medial prefrontal cortex of stressed mice in comparison to controls. Mice of strains C57/6NCrl and DBA/2NCrl, differing in stress response, were exposed to chronic social defeat stress. After the stress paradigm, the mice were assigned as stress-susceptible or stress-resilient, the susceptible mice exhibiting anxiety-like behavior. RNA from OLGs and myelin from the medial prefrontal cortex of the mice was sequenced, and I compared the lncRNA expression levels between stressed and control mice and stress-susceptible and resilient mice using bioinformatic methods. I also assessed modules formed by lncRNAs and protein coding genes correlating in expression in both datasets. I used RT-qPCR to investigate if results from two differentially expressed lncRNAs, Gm37885 and Neat1, replicate in a stress hormone-treated oligodendrocyte cell line. Three hundred and seventy lncRNAs were differentially expressed between stressed mice and controls or stress-susceptible and resilient mice in the OLG dataset and 132 in the myelin dataset. Two hundred and 87 of them overlapped with a protein coding gene in the OLG and myelin datasets, respectively. Sixty-one percent of the differentially expressed lncRNAs were specific to comparisons in the OLG dataset and 73 % in the myelin dataset, but 39 % of the differentially expressed lncRNAs in the OLG dataset and 27 % in the myelin dataset were shared between them. No module of genes with correlating expression levels was associated with stress, but the expression levels of two correlation modules from each dataset differed between strains. The results for one of the differentially expressed lncRNAs, Gm37885, replicated in stressed Oli-neu cells in RT-qPCR. The results of my thesis indicate that multiple lncRNAs are involved in the mouse stress response, as many were differentially expressed and shared between phenotype comparisons. Additionally, significant gene expression differences were observed between strains, which could contribute to the previously reported strain differences in stress susceptibility. The results also suggest a specific role of Gm37885 in GR-mediated stress response. However, the function of Gm37885 remains unknown, and further studies regarding Gm37885 and the other differentially expressed lncRNAs should be carried out to draw conclusions of their contribution to the OLG-mediated stress response.
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