Vukojević, Vanja. Genetics and epigenetics of memory functions : from nematodes to human health and disease. 2012, PhD Thesis, University of Basel, Faculty of Science.
Official URL: http://edoc.unibas.ch/diss/DissB_10182
In contrast to a relatively deep understanding of how memories are formed, is our limited understanding of how these same memories are maintained. Epigenetic modifications of DNA could be crucial for understanding the molecular basis of complex phenotypes. In the second project we tried to underpin the link between traumatic memories and posttraumatic stress disorder (PTSD) in genocide survivors and DNA methylation. Stress induces a complex set of mechanisms that affect the entire organism. The primary function of those changes is to prepare the organism for the direct consequences of stressful events and to ensure a quick return to homeostasis. Additionally, stress is triggering long-term adaptive responses, which result in enhanced memory of stressful events. Failing to recover from the initial response and to keep the adaptive biological alterations under control leads to impaired homeostasis, results in disorders like PTSD. One of the critical symptoms is loss of the auto-regulation of the stress-induced alterations in HPA (hypothalamic-pituitary- adrenal axis) signaling and increased inhibition of the HPA axis. These changes are maintained over a long period of time, although the underlying mechanisms remain unclear. We investigated epigenetic alterations of the glucocorticoid receptor (GR) gene promoter in saliva samples from survivors of the Rwandan genocide. We found a strong, negative correlation of PTSD symptoms like intrusions, avoidance, and PTSD diagnosis with DNA methylation of the GR gene promoter in genocide survivors. Furthermore, the epigenetic changes were specific to the NGFI transcriptional factor-binding site of the GR promoter and also correlate with GR gene expression. Additionally, we detected a significant negative correlation of LINE-1 element methylation with PTSD risk and avoidance symptoms. Together, our data suggests that epigenetic alterations of glucocorticoid receptor gene and genome-wide in LINE-1 elements could be important for pathophysiology of PTSD and may offer new targets for PTSD diagnosis and treatment. This study also suggests an intriguing possibility of using peripheral tissues for finding epigenetic signatures of some life experiences and complex memory processes. Finally, we took one-step ‘’back’’ to the context of the genomic DNA sequence. This revealed the association of genetic variation in the de-novo DNA methyltransferase 3B gene (DNMT3B) with PTSD symptom clusters and risk. Thus, our study suggests a possible mechanism that loops genetic variation and epigenetic mechanisms as driving forces of the phenotypic plasticity, with development, adaptation and disease. But, instead of revealing a simple predictive code that is shared by many genes, in-depth observation of epigenomic patterns highlights the unique complexity of each transcriptional unit and its associated transcriptional regulatory machinery.
|Committee Members:||Papassotiropoulos, Andreas|
|Faculties and Departments:||05 Faculty of Science > Departement Biozentrum > Neurobiology > Molecular Zoology (Reichert)|
|Bibsysno:||Link to catalogue|
|Number of Pages:||100 Bl.|
|Last Modified:||30 Jun 2016 10:51|
|Deposited On:||22 Jan 2013 14:48|
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