TY - CONF
T1 - WHAT CPGS CAN TELL: AN APPROACH TO THE METHYLATION PATTERN OF BDNF PROMOTER IV IN MAJOR DEPRESSION DISORDER AND ITS RELATION TO STRESS
AU - Velásquez Toledo, María Marcela
AU - Gómez-Maquet, Y.
AU - Ferro, E.
AU - Arenas, A.
AU - Uribe, Catalina
AU - Manzanilla, Ileana
AU - Lattig, Claudia
PY - 2019
Y1 - 2019
N2 - Background: The epigenetic mechanisms involved in Major Depressive Disorder are not well understood. Among the genes that have been widely investigated regarding its potential role in depression is the brain-derived neurotrophic factor (BDNF) specifically its promoter IV, whose regulation is activity dependent and mediated by epigenetic mechanisms. While some studies have reported hypermethylation in depressed individuals, others have described opposite patterns. The aim of our study was to determine the methylation pattern of 15 CpG regions within the promoter IV in a clinical sample diagnosed with depression compared to controls. We also wanted to determine if there was a possible mediation of stress on those methylation levels.Methods: We examined blood samples from patients diagnosed with depression (n= 47) and controls (n=43). All participants signed informed consent and completed a series of psychological tests (Mini-International Neuropsychiatric Interview, State-Trait Depression Inventory, State-Trait Anxiety Inventory, Life Events Questionnaire). Early and late stressful events and history of childhood abuse was also evaluated, as well as the value given to certain life events (positive/negative, controllable/no controllable). We measured the global methylation level of BDNF promoter IV and the methylation levels of 15 CpG positions through direct sequencing of bisulfite-treated DNA (BSP) from leukocytes. The DNA methylation analysis was performed using the ESME software. Data analysis included T-test, linear regressions and analysis of variance.Results: We found that the overall methylation of the BDNF promoter IV and the specific methylation levels in three out of 15 CpG sites were significantly different between patients and controls (p < 0.001 each). In all these cases the methylation was higher in controls compared to depressed subjects. A model including the methylation level at two of those three CpG sites (BDNF IV CpG 1: NG_011794.1: 25369 and CpG 9: NG_011794.1: 25469) can explain in 34,6% the categorization as control or depressive patient (p < 0.001). Regarding stress variables, we found that 45% of the patients had a history of abuse, while in controls this value was 19%, varying significantly (p = 0.008). Being exposed to abuse during childhood seems to reduce the methylation level at two CpG sites (BDNF IV CpG 5: NG_011794.1: 25416 and CpG 9) within the promoter. Those same regions appeared to be hypomethylated in subjects exposed to psychological stress and in those that tend to evaluate in a negative way certain life events or who claim to have no control over them. Those two CpG regions contain binding sites for genes as glucocorticoid receptors (GR- Alpha 1) and GATA-1, which have been involved in depressive behavior since it represses synapse-related genes under stressed conditions.Discussion: Our study shows overall and specific hypomethylation patterns within certain CpG sites in the BDNF promoter IV in patients, suggesting that these epigenetic marks could be useful in the diagnosis of this psychiatric disorder. Also, it points out that the stress history and individual responses to life events could be playing an important role in the epigenetic regulation of the promoter. The question remains whether stress response affects epigenetic marks, or if the epigenetic marks affect stress responses. Further research is needed to confirm these results and to clarify which gene networks may be altered by the methylation changes in the promoter.Disclosure: Nothing to disclose.
AB - Background: The epigenetic mechanisms involved in Major Depressive Disorder are not well understood. Among the genes that have been widely investigated regarding its potential role in depression is the brain-derived neurotrophic factor (BDNF) specifically its promoter IV, whose regulation is activity dependent and mediated by epigenetic mechanisms. While some studies have reported hypermethylation in depressed individuals, others have described opposite patterns. The aim of our study was to determine the methylation pattern of 15 CpG regions within the promoter IV in a clinical sample diagnosed with depression compared to controls. We also wanted to determine if there was a possible mediation of stress on those methylation levels.Methods: We examined blood samples from patients diagnosed with depression (n= 47) and controls (n=43). All participants signed informed consent and completed a series of psychological tests (Mini-International Neuropsychiatric Interview, State-Trait Depression Inventory, State-Trait Anxiety Inventory, Life Events Questionnaire). Early and late stressful events and history of childhood abuse was also evaluated, as well as the value given to certain life events (positive/negative, controllable/no controllable). We measured the global methylation level of BDNF promoter IV and the methylation levels of 15 CpG positions through direct sequencing of bisulfite-treated DNA (BSP) from leukocytes. The DNA methylation analysis was performed using the ESME software. Data analysis included T-test, linear regressions and analysis of variance.Results: We found that the overall methylation of the BDNF promoter IV and the specific methylation levels in three out of 15 CpG sites were significantly different between patients and controls (p < 0.001 each). In all these cases the methylation was higher in controls compared to depressed subjects. A model including the methylation level at two of those three CpG sites (BDNF IV CpG 1: NG_011794.1: 25369 and CpG 9: NG_011794.1: 25469) can explain in 34,6% the categorization as control or depressive patient (p < 0.001). Regarding stress variables, we found that 45% of the patients had a history of abuse, while in controls this value was 19%, varying significantly (p = 0.008). Being exposed to abuse during childhood seems to reduce the methylation level at two CpG sites (BDNF IV CpG 5: NG_011794.1: 25416 and CpG 9) within the promoter. Those same regions appeared to be hypomethylated in subjects exposed to psychological stress and in those that tend to evaluate in a negative way certain life events or who claim to have no control over them. Those two CpG regions contain binding sites for genes as glucocorticoid receptors (GR- Alpha 1) and GATA-1, which have been involved in depressive behavior since it represses synapse-related genes under stressed conditions.Discussion: Our study shows overall and specific hypomethylation patterns within certain CpG sites in the BDNF promoter IV in patients, suggesting that these epigenetic marks could be useful in the diagnosis of this psychiatric disorder. Also, it points out that the stress history and individual responses to life events could be playing an important role in the epigenetic regulation of the promoter. The question remains whether stress response affects epigenetic marks, or if the epigenetic marks affect stress responses. Further research is needed to confirm these results and to clarify which gene networks may be altered by the methylation changes in the promoter.Disclosure: Nothing to disclose.
UR - https://www.sciencedirect.com/science/article/pii/S0924977X18305704?via%3Dihub
U2 - 10.1016/j.euroneuro.2018.08.266
DO - 10.1016/j.euroneuro.2018.08.266
M3 - Abstract
SP - S1212
ER -