Seminar Colour Guide:
External Faculty | External Postdoc | Company Representative Science and Society EMBL Distinguished Visitor Lecture Vision2020 Lecture Series Molecular Medicine Seminar | EIPOD Seminar | PSB Seminar | TAC Seminar Hamburg Speaker EMBL-La Sapienza Lecture
|EMBL - Sapienza Lecture||Abstract: Epigenetics of stress allostasis: somatic mechanisms for germ cell programming of offspring development|
Tracy L. Bale, J. Chan, C. Morgan, N.A. Leu, S. Ament, B. Garcia, M. Kane, C.N. Epperson
Parental lifetime exposures to perturbations such as stress, infection, malnutrition, and advanced age have been linked with an increased risk for offspring disease, including a strong association with neurodevelopmental disorders. Our studies have focused on identifying the causal biological mechanisms whereby information in the environment can be transmitted in sperm. In these studies, we demonstrate a causal role for somatic-to-germline transmission of stress information capable of altering fetal neurodevelopment via extracellular vesicles (EVs) in a preclinical model, and we further establish the translational potential of this model in a human cohort. We identified broad histone and transcriptomic alterations in mouse epididymal epithelial cells (EECs) in vivo, with corresponding persistent changes in miRNA and proteomic extracellular vesicle cargo secreted from pure caput EEC populations in vitro. In these studies, the transmission of paternal stress and changes in epigenetic marks only occur following a stress recovery period suggesting a cellular allostatic shift in chromatin programming. Using a transgenic approach, we demonstrated in vivo that the EEC glucocorticoid receptor, a central node of cellular stress mechanisms, serves a key role in this cellular programming where genetic knockdown of this receptor rescued the germline transmission of the offspring stress phenotype. We further established the causal involvement of EEC EVs utilizing intracytoplasmic sperm injection of caput sperm incubated with EVs secreted following stress treatment recovery. Translationally, we have examined similar stress programming changes in human sperm miRNA content. We utilized within and between human subject comparisons of sperm samples and neuropsychiatric perceived stress reports collected repeatedly over six months to identify a distinct miRNA expression pattern from subjects showing a post-stress recovery state.
|EMBL - Sapienza Lecture|