PPARgamma as an architectural regulator of gene expression in endocrine signaling

PPARgamma 作为内分泌信号中基因表达的结构调节因子

• 批准号: 10171574
• 负责人: Laszlo Nagy
• 金额: $ 40.94万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10171574
• 关键词: 3-Dimensional; Adipocytes; Alveolar Macrophages; Animals; Architecture; Atherosclerosis; Binding Sites; Bioinformatics; Biology; Blinded; Cell Differentiation process; Cell model; Cells; Cellular biology; Cholesterol; Chromatin; Chromatin Structure; Chronic; Collaborations; Complex; DNA Binding; Data; Dendritic Cells; Disease; Elements; Endocrine; Enhancers; Fatty Acids; Fibrinogen; Gene Expression; Genes; Genetic Transcription; Genome; Genomics; Human body; Immune system; Inflammation; Inflammatory; Inflammatory Response; Interleukin-4; Laboratories; Learning; Ligand Binding; Ligands; Link; Lipids; Lung; Mediating; Memory; Metabolic Diseases; Metabolism; Methods; Modeling; Molecular Biology; Myeloid Cells; Nuclear Hormone Receptors; PPAR gamma; Pathway interactions; Physiological; Play; Process; Prostaglandins; Proteins; RXR; Regulator Genes; Research; Role; STAT6 gene; Signal Transduction; Testing; Tissues; Transactivation; Transcriptional Regulation; Virus Diseases; Work; cell type; cohesin; dimer; epigenome; epigenomics; gain of function; genome-wide; genome-wide analysis; in vivo; inflammatory milieu; influenza infection; insulin sensitivity; interest; knockout animal; loss of function; macrophage; mutant; overexpression; programs; promoter; receptor; receptor binding; receptor function; research study; response; tissue regeneration; tissue repair; transcription factor; uptake

PROJECT SUMMARY The canonical view of Nuclear Hormone Receptors (NHRs) is that these are ligand-activated transcription factors acting as DNA-bound, lipid-controlled genomic switches. A group of NHRs are acting as heterodimers with the obligate heterodimeric partner Retinoid X Receptor (RXR). One of the key partners of RXR is the Peroxisome Proliferator-Activated Receptor gamma (PPAR). PPAR is viewed as a modified fatty acid and prostanoid regulated transcription factor essential for fat cell differentiation and contributing to lipid metabolite induced transcriptional regulation in many cell types including macrophages. Using traditional ligand centric approaches, we and others were able to identify PPAR target genes and ligand regulated processes including cholesterol uptake and efflux, inhibition of inflammatory responses, regulating insulin sensitivity and promoting tissue repair in macrophages cells. These findings make this receptor a key endocrine regulator of metabolism and inflammation in this cell type. A major weakness of prior research was that it focused solely on ligand- dependent activities of the receptors and did not consider ligand-independent ones. Therefore, there is a substantial gap in our understanding of receptor biology and action. Recent genome-wide determinations of binding sites identified at least two orders of magnitude more genomic binding sites in fat cells and macrophages as regulated genes would necessitate. This prompted us to explore PPAR:RXR cistromes in alternatively polarized macrophages. We have gathered preliminary evidence to suggest that (1) The macrophage PPARγ:RXR cistrome is greatly extended upon IL-4 polarization directed by STAT6; (2) Chromatin-bound PPARγ is predominantly ligand-insensitive in alternatively polarized macrophages; (3) PPARγ:RXR heterodimers are architectural elements of the genome, and (4) the heterodimer confers transcriptional memory via retained gene-enhancer looping. This allows us to formulate new hypotheses as follows: A large fraction of PPAR:RXR heterodimers is ligand-insensitive; (a) Contributing to the epigenome of IL-4 polarized macrophages and provides links between enhancers and promoters via looping utilizing the cohesin complex and/or CTCF; (b) Establishes transcriptional cellular memory and (C) Contributes to macrophage tissue-specification and transcriptional adaptation. We are proposing to test these at three levels. At the chromatin and genome folding level we will determine the epigenomic roles for PPAR. At the cellular level we will determine the role PPAR plays in opening of chromatin and transcriptional memory. Finally at the in vivo level, contribution of PPAR to lung macrophage function and response to viral infection will be explored. The results will likely open up new avenues of research into the epigenomic programming of macrophages with translational potential in chronic inflammatory and metabolic disease and tissue regeneration.

项目概要 核激素受体 (NHR) 的经典观点是它们是配体激活的转录 作为 DNA 结合、脂质控制的基因组开关的因子 一组 NHR 充当异二聚体。 与专性异二聚体伙伴视黄酸 X 受体 (RXR) 的主要伙伴之一是 RXR。 过氧化物酶体增殖物激活受体 γ (PPARα) 被视为一种修饰的脂肪酸。 前列腺素调节转录因子对于脂肪细胞分化至关重要并有助于脂质代谢 使用传统的以配体为中心的方法在包括巨噬细胞在内的许多细胞类型中诱导转录调节。 通过这些方法，我们和其他人能够识别 PPAR- 靶基因和配体调节过程，包括 胆固醇的摄取和流出，抑制炎症反应，调节胰岛素敏感性并促进 巨噬细胞中的组织修复这些发现使该受体成为代谢的关键内分泌调节剂。 先前研究的一个主要弱点是它仅关注配体- 受体的依赖性活性，并且没有考虑配体独立的活性，因此，存在一个。 我们对受体生物学和作用的理解存在重大差距。 结合位点在脂肪细胞中鉴定出至少两个数量级以上的基因组结合位点 巨噬细胞作为调节基因是必要的，这促使我们探索 PPAR-:RXR 顺反子。 我们收集到的初步证据表明（1） 巨噬细胞 PPARγ：RXR 顺反子在 STAT6 引导的 IL-4 极化后大大延伸 (2) 染色质结合的 PPARγ 在交替极化的巨噬细胞中主要是配体不敏感的 (3) PPARγ:RXR 异二聚体是基因组的结构元件，并且 (4) 异二聚体赋予 通过保留的基因增强子循环的转录记忆这使我们能够制定新的假设： 如下： 大部分 PPAR:RXR 异二聚体对配体不敏感； (a) 有助于表观基因组； IL-4 极化巨噬细胞并通过循环利用提供增强子和启动子之间的联系 粘连蛋白复合物和/或 CTCF；(b) 建立转录细胞记忆；(C) 有助于 我们建议在三个水平上测试这些。 在染色质和基因组折叠水平上，我们将确定 PPAR 在细胞中的表观基因组作用。 最后，我们将确定 PPAR 在染色质开放和转录记忆中发挥的作用。 在体内水平上，将探讨 PPAR 对肺巨噬细胞功能和病毒感染反应的贡献。 这些结果可能会为巨噬细胞表观基因组编程的研究开辟新途径 慢性炎症和代谢疾病以及组织再生的转化潜力。

项目成果

The transcription factor EGR2 is the molecular linchpin connecting STAT6 activation to the late, stable epigenomic program of alternative macrophage polarization.

转录因子 EGR2 是将 STAT6 激活与巨噬细胞极化的晚期稳定表观基因组程序连接起来的分子关键。

• 发表时间: 2020
• 影响因子: 10.5
• 作者: Daniel, Bence;Czimmerer, Zsolt;Halasz, Laszlo;Boto, Pal;Kolostyak, Zsuzsanna;Poliska, Szilard;Berger, Wilhelm K;Tzerpos, Petros;Nagy, Gergely;Horvath, Attila;Hajas, György;Cseh, Timea;Nagy, Aniko;Sauer, Sascha;Francois;Szatmar
• 通讯作者: Szatmar

Transcriptional repression shapes the identity and function of tissue macrophages.

转录抑制决定了组织巨噬细胞的特性和功能。

• 发表时间: 2021
• 影响因子: 2.6
• 作者: Bene, Krisztian;Halasz, Laszlo;Nagy, Laszlo
• 通讯作者: Nagy, Laszlo

Myeloid cell diversification during regenerative inflammation: Lessons from skeletal muscle.

再生炎症过程中的骨髓细胞多样化：骨骼肌的教训。

• 发表时间: 2021
• 影响因子: 7.3
• 作者: Patsalos, Andreas;Tzerpos, Petros;Wei, Xiaoyan;Nagy, Laszlo
• 通讯作者: Nagy, Laszlo

An effective method for culturing functional human corneal endothelial cells using a xenogeneic free culture medium.

一种使用异种游离培养基培养功能性人角膜内皮细胞的有效方法。

• 发表时间: 2023-11-09
• 影响因子: 4.6
• 作者: Alonso;Vázquez, N;Chacón, M;Caballero;Del Olmo;Suárez, C;Alfonso;Fernández;Nagy, L;Merayo;Meana, A
• 通讯作者: Meana, A

The BACH1-HMOX1 Regulatory Axis Is Indispensable for Proper Macrophage Subtype Specification and Skeletal Muscle Regeneration.

BACH1-HMOX1 调节轴对于正确的巨噬细胞亚型规范和骨骼肌再生是不可或缺的。

• 发表时间: 2019
• 作者: Patsalos, Andreas;Tzerpos, Petros;Halasz, Laszlo;Nagy, Gergely;Pap, Attila;Giannakis, Nikolas;Lyroni, Konstantina;Koliaraki, Vasiliki;Pintye, Eva;Dezso, Balazs;Kollias, George;Spilianakis, Charalampos G;Nagy, Laszlo
• 通讯作者: Nagy, Laszlo