Directing the Epigenetic Factors in Maternal Breast Milk Exosomes Authors: Kacie D. Waiters, Samaneh Karami, Yunus M. Ahmadi, Frank X. Placencia, Tasneem Bawa-Khalfe Human breast milk is the nutritional gold-standard for optimum neonatal development. In addition to its nutritional benefits, breast milk serves as a transmission media for epigenetic factors from mother to infant. These factors in maternal breast milk direct the infant’s genome to support normal early-life development and future health. This wide-spanning impact on infant health validates the need to better understand the epigenetic composition of breast milk. The mother’s breast cell selects specific epigenetic biomolecules to actively sort into protective extracellular vesicles or exosomes and expel into breast milk. Previous studies show human breast milk exosomes include an extensive repertoire of regulatory microRNAs (miRs) that are transferred from the mother to the recipient infant cells. Several large scale in silico and limited experimental studies indicate miRs in milk exosomes fluctuate to accommodate for the changing needs of the growing infant. These findings raise an unresolved question: how does the mother’s body select the optimal miRs for transport into breast milk exosomes. Our new findings indicate estrogen and the estrogen receptor, ESR1, levels orchestrate the oscillating composition of breast milk exosomes. It is well-established the levels of estrogen and ESR1 vary postpartum. We now report that in breast cells, an estrogen-dependent regulatory system selects miRs with a defined consensus sequence for subsequent exosomal transport. Our ongoing work tests the hypothesis postpartum maternal estrogen levels modulate exosomal miRs to impact the genetic landscape of recipient infant cells. Findings from these studies will expand our understanding of the maternal-infant epigenetic link established through breast milk. In addition, we anticipate the results may serve as a foundational resource to establish a miR-based screen to match maternal breast milk to infant needs.