Impact of Childhood Abuse on Histone Modification Landscape in the Amygdala

Marc-Aurèle Chay1, Pierre-Eric Lutz1, Alexandre Bramoulle1, Jean-François Theroux1, Tony Kwan2, Adriana Redensek2, Tomi Pastinen2, Carl Ernst1, Gustavo Turecki1

1. McGill Group for Suicide Studies, McGill University, Montreal, QC; 2. Genome Quebec Innovation Centre, McGill University, Montreal, QC

Background: Victims of childhood abuse often develop maladaptive aggressive traits and suicidal behaviours into adulthood, which seem to be accompanied with structural changes in the amygdala. Recent studies demonstrate that early-life events have long-lasting impacts on gene expression and behaviour through epigenetic mechanisms such as histone post-translational modifications.

Methods: We use next generation sequencing methods: RNA-seq and Chip-seq for six histone marks to obtain a more complete view of early-life adversity-induced changes in the amygdala of suicide completers. Post-mortem brain tissue of 20 suicide completers with a history of childhood abuse were compared to 17 controls. We identified changes in histone modification patterns using two separate statistical approaches, interrogating either each histone mark separately or characterizing differences in chromatin states. These results were then integrated with gene expression data to determine the genes/gene categories showing the highest levels of change.

Results: We identified a large number of regions showing differences in histone modification enrichment or chromatin states between our controls and suicide-abused subjects. Gene Ontology analyses revealed four major biological processes consistently affected. These gene categories were related to the immune, GTPase, cytoskeleton and apoptosis systems. Differential gene expression analysis showed a dysregulation in similar pathways, and a high overlap was found between expression and histone modification analyses. From these genome-wide results, 12 candidate genes were identified, and will be validated using a targeted approach.

Conclusion: Combining histone modification and gene expression data, we show genome wide epigenetic changes in multiple gene systems in the amygdala caused by childhood abuse and suicide.