Understanding the role of histone3 lysine4 trimethylation in neontal innate immune development under normal and inflammatory conditions

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PROJECT SUMMARY/ABSTRACT Neonates have dampened expression of pro-inflammatory cytokines and difficulty clearing pathogens, making them uniquely susceptible to infections. This is a worldwide health problem, with neonatal infections contributing to nearly one million deaths each year. The factors controlling neonatal specific immune responses and how and when they transition to more mature responses are poorly understood. Neonates rely heavily on innate immune responses to fight infections due to major defects in their adaptive immune system. Monocytes and macrophages are central to innate immune responses by sensing pathogens and initiating an inflammatory cascade that directs their clearance. Although both neonatal and adult monocytes/macrophages contain the same genetic code, they exhibit dramatic differences in pathogen-induced gene expression. Post- translational histone modifications can regulate gene transcription by influencing chromatin structure and accessibility, and likely play a role in this. Monocytes/macrophages demonstrate a developmental stage- specific increase in the H3K4 methyltransferase MLL1 with an associated gain in the activating histone modification histone 3 lysine 4 trimethylation (H3K4me3) at promoter sites of immunologically important genes as development progresses from extremely preterm neonate to adult. This gain allows for increasingly robust inflammatory responses as development advances. Microbial colonization of the skin and gastrointestinal tract occurs after birth and is associated with type 1 interferon expression, which is believed to guide immune system maturation and prevent detrimental pathogen responses. Chorioamnionitis is an inflammatory process affecting neonates around the time of birth, which negatively impacts immune system development and predisposes exposed neonates to long-term immune-related complications. The central hypothesis of this proposal is that neonatal monocytes/macrophages are largely un-patterned with H3K4me3 due to lack of in utero microbial exposure, and that postnatal microbial exposure stimulates low grade type 1 IFN expression which drives MLL1 expression and directs macrophage H3K4me3 deposition in a developmental stage-specific manner. Chorioamnionitis exposure stimulates a developmentally inappropriate level of type 1 interferon expression, which results in dysregulated MLL1 expression and global remodeling of the neonatal monocyte/macrophage landscape with subsequent dysfunctional monocyte/macrophage responses. This hypothesis will be investigated via the following specific aims: 1) Characterize normal human monocyte H3K4me3 patterning during infancy and early childhood and determine how developmental stage-specific H3K4me3 monocyte patterning impacts chromatin accessibility and gene expression, 2) Determine the requirement and sufficiency of type 1 interferons in MLL1-driven H3K4me3 placement in murine macrophage development and function, and 3) Determine the roles of type 1 interferons and MLL1 in chorioamnionitis-induced murine macrophage H3K4me3 remodeling and subsequent function.