Transcriptional Regulators in Aging Macrophages

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As key governors of tissue integrity, macrophages are implicated in many age-related diseases. Macrophages are a plastic myeloid immune cell type found in nearly every tissue of the body where they perform critical functions for homeostasis. Tissue-resident macrophages adapt to perform specific functions through the action of tissue-specific transcription factors (TFs) that respond to signals in the local environment. In combination with cell-type-specific TFs, they specify a distinct epigenomic landscape leading to tissue-specific gene expression. Changes to the macrophage environment due to systemic inflammation and other signals in aging lead to a decline in macrophage function. In order to develop preventative strategies, we need a better understanding of how macrophages are altered in aging. However, parsing out the exact signals responsible and their indirect effects in an intractable problem. Instead, we have the opportunity to take advantage of functional genomic approaches to identify the downstream regulators, such as TFs and enhancers, that lead to age-related dysregulation. In this proposal, we will use macrophages in the synovium of murine ankle joints and computational approaches to model an aging tissue. The synovial compartment largely consists of long-lived tissue-resident macrophages but the contribution of monocyte-derived cells that originate in the bone marrow increases with age. Our preliminary analysis of the age-associated epigenomic landscape of bone marrow monocytes revealed increased activity of chromatin remodelers and decreased activity of cell-type-specific TFs. Similarly, we observe a decrease in tissue-resident synovial macrophages in the aging joint and a shift in the transcriptional profile towards monocyte-derived macrophages. Thus, we hypothesize that the aging synovial macrophage phenotype is driven by replacement with monocyte-derived cells that fail to acquire tissue- resident regulators due to epigenomic reprogramming by the aging bone marrow micro-environment. In Aim 1, we will assess age-associated changes to the synovial macrophage compartment over time. We will perform ATAC-seq, ChIP-seq, and scRNA-seq on monocyte-derived and tissue-resident macrophages subpopulations to profile their epigenomic landscape across time. By a combination of clustering and supervised approaches, we will identify temporal patterns of epigenomic reprogramming and implicate specific TFs that drive aging in each subpopulation. In Aim 2, we will quantify the impact of cell intrinsic vs. bone marrow micro- environment on aging monocyte-derived macrophages. Through analysis of their epigenomic profile, we will identify key enhancers and TFs in their genomic context. Moreover, we will compare the results with additional chimeras where TNF, one of the key signals in the aging environment, and its receptors are blocked. Together, these aims will identify key downstream regulators that drive macrophage dysfunction in aging mice with the ultimate goal of translating of our findings to human patients. Our results will provide a better understanding of the aging immune system and potential targets for interventions that improve health in aging.