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Glucocorticoid-regulated transcription networks in macrophage biology

巨噬细胞生物学中糖皮质激素调节的转录网络

基本信息

批准号：
10670174
负责人：
INEZ ROGATSKY
金额：
$ 49.28万
依托单位：
HOSPITAL FOR SPECIAL SURGERY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10670174
关键词：
ATAC-seq Adipocytes Adipose tissue Amputation Anti-Inflammatory Agents Binding Sites Biology Blood Vessels Bone Marrow Cells Chromatin Chronic Complex Data Disease EP300 gene Enhancers Environment Equilibrium Event Exposure to Family Fatty Acids Fatty acid glycerol esters GKLF protein GRIP1 gene Gene Expression Gene Expression Profile Genes Genetic Transcription Glucocorticoid Receptor Glucocorticoids Goals Growth Health Heart Diseases Histopathology IL4 gene ITGAX gene Immune Impaired wound healing In Vitro Individual Inflammation Inflammatory Insulin Interleukin 4 Receptor Interleukin-1 beta Interleukin-4 Lead Link Liver Macrophage Maintenance Maps Mediating Mediator Metabolic Metabolic Diseases Metabolic dysfunction Molecular Mus NCOA2 gene NRIP1 gene Non-Insulin-Dependent Diabetes Mellitus Nuclear Nuclear Receptors Obesity Outcome PPAR gamma Pathogenesis Pathogenicity Pathway interactions Phenotype Physiological Population Property Proteins Research Role STAT6 gene Signal Induction Signal Transduction Skin Specific qualifier value Stimulus Structure Surface TNF gene Testing Thinness Transforming Growth Factor beta Vascular Endothelium Wound models biomarker identification blood damage chemokine chronic ulcer cofactor comorbidity cytokine epigenome epigenomics fatty acid oxidation genome-wide in vivo metabolic profile monocyte novel oxidation programs promoter receptor response single-cell RNA sequencing skin damage tissue repair transcription factor transcriptome transcriptome sequencing transcriptomics uptake virtual wound wound healing

项目摘要

Macrophage (MΦ)-driven inflammation is central to the pathogenesis of metabolic disease in adipose tissue, liver, vascular endothelium and the skin. However, MΦ are extremely diverse in their ontogeny, epigenomes, transcriptomes and function. Indeed, `lean' adipose tissue M2-like MΦ are anti-inflammatory, facilitate fatty acid oxidation and sensitize adipocytes to insulin. In the skin, homeostatic tissue-repairing MΦ are essential responders to damage, and defective wound healing is a striking comorbidity of metabolic disorder. Signals for homeostatic MΦ programming (e.g., interleukin [IL]4 and glucocorticoids [GC]) initiate via cognate transcription factors (STAT6 and the GC nuclear receptor [GR]) gene expression cascades that ultimately converge upon the `master regulator' kruppel-like factor (KLF)4 that activates many M2-specific genes. Conversely, M1-like inflammatory MΦ bear the transcriptional signature of nuclear factor (NF)κB and overproduce mediators of chronic inflammation (TNF, IL1β, iNOS, Ccl2). Although an M1/M2 imbalance is strongly linked to metabolic dysfunction and impaired wound healing, the specific epigenomic and transcriptional networks underlying homeostatic polarization of different M2 populations remain obscure. In fact, only limited data exist on the mechanisms of KLF4 function as a transcription factor, and virtually none on its genome-wide distribution or role in programming individual M2 subsets. Unexpectedly, we discovered that a nuclear receptor cofactor – the GR-interacting protein (GRIP)1 – serves as a coactivator for KLF4 facilitating M2 polarization of mouse bone marrow-derived MΦ. Given that Klf4 itself is a GR target, GRIP1 could mediate the multi-level integration of M2 transcription programs in vivo when MΦ encounter distinct polarizing signals, e.g., GC and IL4, simultaneously. The objective of this application is to understand the epigenomics, transcriptomics and higher order chromatin interactions of homeostatic MΦ in vitro and in vivo. Our central hypothesis is that GC and IL4 create partially overlapping yet distinct chromatin environments in homeostatic MΦ, and that by serving as a shared cofactor for GR and KLF4, GRIP1 facilitates the physiologically relevant functional convergence of M2- like transcription programs in vivo. Our Specific Aims are to: 1) Dissect the global contribution of GRIP1 to GR and KLF4 enhancer formation and to the core M2-like transcription program through genome-wide approaches in GC- and IL4-polarized MΦ ex vivo; 2) Assess the impact of GRIP1 loss on the phenotypic and metabolic properties of homeostatic MΦ ex vivo and on their ability to undergo epigenomic and transcriptional programming, and support tissue repair in vivo; 3) Chart the first map of higher-order chromatin and GRIP1- dependent enhancer-promoter interactions in homeostatic MΦ, and identify the mechanistic determinants of the GRIP1:KLF4 cross-talk. The successful completion of this project will yield a comprehensive analysis of global chromatin interactions, the core transcriptome as well as GRIP1-dependent molecular mechanisms of homeostatic programming of MΦ which, unlike inflammatory MΦ activation, remains poorly defined.

巨噬细胞（MΦ）驱动的炎症是脂肪组织代谢疾病发病机制的核心，肝脏、血管内皮和皮肤。然而，MΦ在其个体发育、表观基因组、转录组和功能。事实上，“瘦”脂肪组织M2样MΦ是抗炎的，促进脂肪酸氧化并使脂肪细胞对胰岛素敏感。在皮肤中，稳态组织修复MΦ是必需的损伤的应答者和有缺陷的伤口愈合是代谢紊乱的显著共病。信号稳态MΦ编程（例如，白细胞介素[IL]4和糖皮质激素[GC 因子（STAT 6和GC核受体[GR]）基因表达级联，最终聚集在激活许多M2特异性基因的“主调节因子”Kruppel样因子（KLF）4。相反，M1型炎性MΦ携带核因子（NF）κB的转录特征，并过度产生慢性炎症（TNF、IL 1 β、iNOS、Ccl 2）。尽管M1/M2失衡与代谢紊乱密切相关，功能障碍和受损的伤口愈合，特定的表观基因组和转录网络的基础不同M2种群内稳态极化仍不清楚。事实上，只有有限的数据存在于 KLF 4作为转录因子发挥作用的机制，几乎没有关于其全基因组分布或在编程单个M2子集中的作用。出乎意料的是，我们发现一种核受体辅因子-- GR相互作用蛋白（GRIP）1 -作为KLF 4的共激活剂，促进小鼠骨的M2极化骨髓MΦ。考虑到Klf 4本身是GR靶标，GRIP 1可以介导M2的多水平整合当MΦ遇到不同的极化信号时，GC和IL 4，同时。这个应用程序的目的是了解表观基因组学，转录组学和更高的顺序体内外稳态MΦ的染色质相互作用。我们的中心假设是GC和IL 4 在稳态的MΦ中创造部分重叠但不同的染色质环境，并且通过充当一个 GRIP 1是GR和KLF 4的共同辅因子，它促进了M2-KLF 4的生理相关功能收敛。就像体内的转录程序一样。我们的具体目标是：1）剖析GRIP 1对GR的全球贡献和KLF 4增强子的形成，并通过全基因组方法与核心M2样转录程序在离体GC和IL 4极化的MΦ中; 2）评估GRIP 1丢失对表型和代谢的影响离体稳态MΦ的性质及其进行表观基因组和转录的能力编程，并支持体内组织修复; 3）绘制高阶染色质和GRIP 1的第一个图谱- 稳态MΦ中依赖性增强子-启动子相互作用，并确定其机制决定因素 GRIP 1：KLF 4串扰。该项目的成功完成将产生一个全面的分析，全球染色质相互作用，核心转录组以及GRIP 1依赖的分子机制，与炎性MΦ活化不同，MΦ的稳态编程仍然不清楚。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Preparing the first responders: building the inflammatory transcriptome from the ground up.

DOI：
10.1016/j.molcel.2014.03.038
发表时间：
2014-04-24
期刊：
MOLECULAR CELL
影响因子：
16
作者：
Rogatsky, Inez;Adelman, Karen
通讯作者：
Adelman, Karen

Gene-specific mechanisms direct glucocorticoid-receptor-driven repression of inflammatory response genes in macrophages.

基因特异性机制直接糖皮质激素受体驱动的巨噬细胞炎症反应基因的抑制

DOI：
10.7554/elife.34864
发表时间：
2018-02-09
期刊：
eLife
影响因子：
7.7
作者：
Sacta MA;Tharmalingam B;Coppo M;Rollins DA;Deochand DK;Benjamin B;Yu L;Zhang B;Hu X;Li R;Chinenov Y;Rogatsky I
通讯作者：
Rogatsky I

There goes the neighborhood: Assembly of transcriptional complexes during the regulation of metabolism and inflammation by the glucocorticoid receptor.