Unorthodox Transcriptional Mechanisms of Lipid-Sensing Nuclear Receptors in Macrophages: Are We Opening a New Chapter?
Unorthodox Transcriptional Mechanisms of Lipid-Sensing Nuclear Receptors in Macrophages: Are We Opening a New Chapter?
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DOI：
10.3389/fendo.2020.609099
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发表时间：
2020
影响因子：
5.2
通讯作者：
Nagy L
中科院分区：
文献类型：
--
作者：
Czimmerer Z;Halasz L;Nagy L
过去30年的研究表明，脂质激活的核受体在代谢和免疫之间形成桥梁，整合了先天免疫细胞中的代谢和炎症信号。配体诱导的直接转录激活和基于蛋白质-蛋白质相互作用的反式阻遏被确定为配体核受体介导的转录调控的最常见机制。然而，整合不同的下一代测序为基础的方法，包括染色质免疫沉淀，然后测序和全球运行测序允许在全基因组水平上研究DNA结合和配体反应的核受体。令人惊讶的是，这些研究提出了一个概念，即大部分的脂质敏感核受体顺反不一定响应配体激活。虽然核受体顺反的配体不敏感部分的生物学作用在很大程度上是未知的，最近的研究结果表明，它们可能在染色质结构的组织中发挥作用，在转录记忆的调节中，以及在巨噬细胞中对其他微环境信号的反应的表观基因组修饰。在这篇综述中，我们将提供一个概述，并讨论我们的理解的脂质激活的核受体介导的非经典或非正统的行动在巨噬细胞的最新进展。
Work over the past 30 years has shown that lipid-activated nuclear receptors form a bridge between metabolism and immunity integrating metabolic and inflammatory signaling in innate immune cells. Ligand-induced direct transcriptional activation and protein-protein interaction-based transrepression were identified as the most common mechanisms of liganded-nuclear receptor-mediated transcriptional regulation. However, the integration of different next-generation sequencing-based methodologies including chromatin immunoprecipitation followed by sequencing and global run-on sequencing allowed to investigate the DNA binding and ligand responsiveness of nuclear receptors at the whole-genome level. Surprisingly, these studies have raised the notion that a major portion of lipid-sensing nuclear receptor cistromes are not necessarily responsive to ligand activation. Although the biological role of the ligand insensitive portion of nuclear receptor cistromes is largely unknown, recent findings indicate that they may play roles in the organization of chromatin structure, in the regulation of transcriptional memory, and the epigenomic modification of responsiveness to other microenvironmental signals in macrophages. In this review, we will provide an overview and discuss recent advances of our understanding of lipid-activated nuclear receptor-mediated non-classical or unorthodox actions in macrophages.
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