Epigenetic insights into stress vulnerability in mouse models

Abstract While neuropsychiatric disorders are highly heritable, it is well recognized that environmental factors, such as chronic stress, contribute to the risk of developing mood-related psychiatric disorders. However, the epigenetic mechanisms underlying stress vulnerability and the pathogenic mechanisms linking stress to increased susceptibility of psychiatric conditions are not well understood. Based on our recent discovery that the transcription factor Yin Yang 1 (YY1) and YY1 regulon are selectively down-regulated in cortical excitatory neurons upon chronic stress exposure, and selective ablation of Yy1 in excitatory neurons enhances stress sensitivity in both male and female mice, we propose to employ a combination of genetic, genomic, molecular, and behavioral approaches to investigate the epigenetic mechanisms by which chronic stress elicits maladaptive behaviors and test a specific hypothesis that the stress related glucocorticoid receptor (GR)-YY1 reciprocal regulation contributes to stress vulnerability in mice. With currently available state-of-the-art genomic technologies and our newly developed, genetically modified mouse tools, we hope to improve our understanding of the underlying causes of stress-related psychiatric disorders and provide the necessary foundation for better diagnosis and intervention.