BET Proteins in Early Life Stress-induced Cardiovascular Disease

Early life stress (ELS) in childhood due to physical or sexual violence, parental neglect, or trauma has been recently associated with an increased risk of cardiovascular disease in later life. However, the mechanisms linking ELS to cardiovascular impairment remain unexplored. Epigenetic regulation of gene expression is emerging as a pivotal process linking environmental exposure to disease phenotypes. Among chromatin remodelers, BET (bromodomain and extra-terminal) proteins are key regulators of gene transcription through their binding to acetylated lysine residues on histone tails via tandem bromodomains. Own preliminary data suggest that BET proteins are heavily involved in transcriptional programs relevant to cardiovascular disease. In BETonSTRESS, I hypothesize that childhood adversities alter the epigenetic landscape thus leading to maladaptive transcriptional programs and cardiovascular disease development. Using a mouse model of ELS and longitudinal cohorts, I will: i) investigate the chromatin landscape, BET function and cell-specific transcriptional changes in the ELS mouse heart; ii) test the effects of BET editing on cardiovascular function in ELS mice; iii) study the impact of stress-mitigating strategies (environmental enrichment) in preventing chromatin remodeling, BET activation and cardiac dysfunction in ELS mice; iv) test the cardiovascular predictive value of BET-related circulating biomarkers in two longitudinal cohorts of ELS-exposed individuals. The preliminary data suggest a prominent role of BET proteins in epigenetic remodeling and cardiac dysfunction in ELS mice.BETonSTRESS will: i) unveil the role of BET proteins and chromatin remodeling in ELS-induced cardiovascular dysfunction; ii) set the stage for stress-mitigating approaches and epigenetic therapies in the setting of ELS; iii) identify epigenetic biomarkers of cardiovascular disease in ELS individuals; iv) increase the awareness on the negative role of ELS in the society.