CUT&RUN-seq: Stress increases sperm respiration and motility in mice and men

Cumulative stress and adverse experiences precipitate changes in overall health, disrupting homeostasis and increasing disease. Stress is a known driver of allostatic changes, allowing for cellular adaptation in the face of environmental challenges. However, the molecular mechanisms regulating allostasis and long-term changes in intra- and intercellular signaling important for health are not clear. In males, chronic stress produces lasting changes in epididymal epithelial cell (EEC) intercellular signaling and extracellular vesicle (EV) composition important for sperm maturation. Here we used this system to assess the mechanisms regulating allostasis and the role of EVs to impact downstream target cell physiology and function. We found that prior corticosterone treatment decreased EEC energy requirements and altered mitochondrial ultrastructure, with changes in the cellular set point involving the mitochondrial complex I. CUT&RUN sequencing and gene co-expression network analysis separately identified significant epigenetic and transcriptomic reprogramming important for mitochondrial function. We found this new EEC allostatic state regulated EV intercellular communication with sperm, where EVs isolated from stress EECs increased sperm mitochondrial respiration, ultimately increasing sperm motility. These data support a signaling pathway by which a new cellular allostatic setpoint can be communicated to other cells, affecting their function.