Transcriptional Regulators in Aging Macrophages

衰老巨噬细胞中的转录调节因子

• 批准号: 10436975
• 负责人: Deborah Rachelle Winter
• 金额: $ 58.91万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10436975
• 关键词: ATAC-seq; Adopted; Age; Aging; Arthritis; Bone Marrow; Cells; ChIP-seq; Chimera organism; Data; Degenerative polyarthritis; Development; Disease; Downstream Enhancer; Enhancers; Environment; Exhibits; Functional disorder; Future; Gene Expression; Gene Expression Profile; Genetic Transcription; Genomic approach; Genomics; Goals; Health; Heterogeneity; Homeostasis; Human; Immune; Immune system; Immunity; Intervention; Joints; Lead; Link; Modeling; Molecular; Mus; Myelogenous; Patients; Pattern; Phenotype; Population; Prevention strategy; Process; Publishing; Regulation; Regulatory Element; Role; Signal Transduction; Specific qualifier value; Supervision; Synovial Membrane; TNF gene; Testing; Time; Tissue-Specific Gene Expression; Tissues; To specify; Translating; Transplantation; Tumor Necrosis Factor Receptor; Wild Type Mouse; Work; age related; aged; ankle joint; cell type; chromatin remodeling; computer framework; epigenomics; functional genomics; improved; macrophage; monocyte; mouse model; receptor; residence; single-cell RNA sequencing; systemic inflammatory response; therapeutic target; transcription factor; transcriptome sequencing

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.

巨噬细胞作为组织完整性的关键调节者，与许多年龄相关的疾病有关。巨噬细胞 是一种可塑的髓系免疫细胞类型，几乎存在于身体的每一个组织中，在那里它们执行关键的 动态平衡的功能。组织驻留的巨噬细胞通过这种作用适应执行特定的功能 对局部环境中的信号做出反应的组织特异性转录因子(TF)。结合使用 细胞类型特异的转录因子，它们指定了导致组织特异性基因表达的独特的表观基因组图景。 在衰老过程中，由于全身炎症和其他信号导致巨噬细胞环境的变化导致 巨噬细胞功能下降。为了制定预防策略，我们需要更好地了解 巨噬细胞在衰老过程中的变化。然而，解析出确切的负责信号及其间接 在一个棘手的问题上的影响。相反，我们有机会利用功能基因组 确定下游调节因子，如转录因子和增强剂，导致与年龄相关的方法 监管失调。在这个方案中，我们将在小鼠脚踝关节的滑膜中使用巨噬细胞 对老化组织进行建模的计算方法。滑膜小室主要由长寿的 组织驻留的巨噬细胞，但起源于骨髓的单核细胞的贡献 随年龄增长。我们对年龄相关的骨髓表观基因组图谱的初步分析 单核细胞显示染色质重构体活性增加，细胞类型特异性转录因子活性降低。 类似地，我们观察到老化关节中组织驻留的滑膜巨噬细胞减少和关节移位。 单核细胞来源的巨噬细胞的转录图谱。因此，我们假设老化的滑膜 巨噬细胞表型是由无法获得组织的单核细胞来源的细胞替代而来的。 由老化的骨髓微环境引起的表观基因组重编程所致的驻留调节因子。在……里面 目的1，我们将评估与年龄相关的滑膜巨噬细胞随时间的变化。我们会 对单核细胞来源和组织驻留的巨噬细胞执行atac-seq、Chip-seq和scRNA-seq 亚群来描绘他们的表观基因组图景。通过集群和监督的组合 方法，我们将确定表观基因组重编程的时间模式，并暗示特定的TF 在每个亚群中推动老龄化。在目标2中，我们将量化细胞固有与骨髓微结构的影响。 环境对老化的单核细胞来源的巨噬细胞的影响。通过分析他们的表观基因组图谱，我们将 在基因组环境中确定关键的增强子和转录因子。此外，我们会将结果与其他 在这种嵌合体中，衰老环境中的关键信号之一肿瘤坏死因子及其受体被阻断。一起， 这些目标将确定导致巨噬细胞功能障碍的关键下游调节因子 最终目标是将我们的发现转化为人类患者。我们的结果将为我们更好地理解 老化的免疫系统和改善老龄健康的干预措施的潜在目标。