Epigenetic Regulation of FosB in Mast Cells 2306012

Abstract

Abstract Introduction Early life adversity (ELA) leads to increased chances of developing proinflammatory disorders like allergy later in life. Mast cells are innate immune cells that regulate immune response to infection and allergens through the release of inflammatory mediators such as cytokines and histamines. ELA causes increased mast cell numbers and activity in the dura mater in adult mice. FosB is highly expressed in active mast cells and acts as a negative feedback mechanism to limit mast cell activation. This raises the question of whether ELA can epigenetically regulate the expression of the FosB gene later in life. Methods Wildtype mice undergo Neonatal Maternal Separation plus Early Weaning (NMSEW) as a model of ELA. Litters are either separated for 3 hours daily in individual cups from postnatal days 1-16, weaned early at day 17, and left in their home cages until adulthood, or normally weaned at day 25 and left in their home cages. Upon adulthood, bone marrow is differentiated into bone marrow derived mast cells (BMMCs) and then sensitized and activated by IgE-DNP (allergic activation), and FosB expression assessed by qPCR and Western Blot, and histone modifications are assessed by CUT&RUN. Results We see that NMSEW increases ΔFosB expression in BMMCs derived from adult mice. This increase is seen both basally and following allergic activation. We are now in the process of using CUT&RUN to determine the changes in FosB gene structure at various stages of development following NMSEW. Conclusion Increased FosB could represent a crucial epigenetic and transcriptional mechanism regulating mast cell activation following early life adversity, potentially inhibiting further mast cell activation and limiting the effects of ELA on inflammatory disease later in life. Funding Source NIH National Institute of Allergy and Infectious Diseases, NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)