Suicidal behaviors are a major public health issue that severely impact our societies. In particular, it has been clearly shown that social interactions, support by friends and family members, as well as favorable social environments are protective factors against the risk of suicide. Conversely, detrimental social experiences, including social rejection or bullying, are important factors that contribute to that risk. It is critical therefore, to better characterize and understand the biological mechanisms that may mediate part of these effects.
In the present project, we will address this issue by developing a research program dedicated to the understanding of the role of epigenetic processes in the relationship between suicide attempt and social adversity. Epigenetics can be defined as molecular mechanisms that control the organization and expression of genes in response to life experiences, and are ideally suited to explain how adverse life experience may contribute to suicide.
Here, building on extensively characterized cohorts of patients, archived biological samples and cutting-edge high-throughput methodologies, we will first identify epigenetic adaptations that can be detected as a function of past histories of suicide attempt in peripheral blood samples collected from 2 French clinical cohorts (n=207 subjects in total). We will focus our analyses on DNA methylation, a major epigenetic mark that corresponds to a chemical modification of the DNA and controls gene expression, using EPIC arrays as a cost-effective approach covering the entire human genome.
In a second step, we will test the hypothesis that measures of biological variables in peripheral tissues may reflect molecular mechanisms occurring in the brain. Accordingly, we will determine whether genomic regions showing differential methylation in blood are also affected in the brain of people who died by suicide, either at DNA methylation or gene expression level. This will be done by mining a unique database of molecular adaptations that we generated over recent years, during our genome-wide studies of post-mortem brain tissues.
Third, we will characterize how such epigenetic changes modulate molecular reactivity to social stress, using the well-established Trier Social Stress Test. Using blood samples collected before and 1 hour after completion of this test (in n=79 subjects in total), we will directly assess whether DNA methylation changes that associate with suicide attempt control the expression of nearby genes during the stressful experience, using our operational medium-throughput methodology, targeted bisulfite sequencing.
Overall, the proposed studies have the potential to significantly advance our knowledge on epigenetic mechanisms contributing to suicidal behaviors and the associated vulnerability to social adversity. They may open new perspectives for the development of clinically relevant biomarkers, and guide the identification of individuals most at risk, who would benefit more from intensive care plans.
