Early Life Stress Primes Future Stress Susceptibility via Epigenetic Priming in the Brain

Abstract

Early life stress (ELS) has been found to be a major risk factor for increased sensitivity to adult stress and for other psychiatric diseases. Studies show that ELS during a critical development period in mice increases depression-like behaviors specifically after subsequent exposure to stress in adulthood, suggesting that ELS “primes” the brain to be more sensitive to adult stress. Specifically, we hypothesize that ELS reorganizes the epigenetic state to facilitate — or prime gene expression in response to future adult stress. Such priming can be achieved by opening chromatin which increases accessibility to DNA and has a greater potential to be altered. Open chromatin is marked by the histone modification H3K4me1 (monomethyl-histone-3-lysine-4) which is deposited by the enzyme SETD7. Here, we used a viral construct to artificially remodel the epigenetic state to test whether increased H3K4me1 primes a response to adult stress. We established that elevated Setd7 does increase H3K4me1 deposition in the brain, alters behavioral responses to stress, and changes transcription following adult stress. Ultimately, this research has immense potential for innovations in treatment that can mitigate the negative effects of childhood adversity such as stress susceptibility and greater risk for mental health illnesses.