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染色质可及性分析鉴定转录因子 ETV5 为肥胖症脂肪组织巨噬细胞激活的抑制剂。

Chromatin accessibility analysis identifies the transcription factor ETV5 as a suppressor of adipose tissue macrophage activation in obesity.

机构信息

Chronic Disease Laboratory, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China.

Institute of Artificial Intelligence, Hefei Comprehensive National Science Center, Hefei, Anhui, China.

出版信息

Cell Death Dis. 2021 Oct 29;12(11):1023. doi: 10.1038/s41419-021-04308-0.

DOI:10.1038/s41419-021-04308-0
PMID:34716308
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8556336/
Abstract

Activation of adipose tissue macrophages (ATMs) contributes to chronic inflammation and insulin resistance in obesity. However, the transcriptional regulatory machinery involved in ATM activation during the development of obesity is not fully understood. Here, we profiled the chromatin accessibility of blood monocytes and ATMs from obese and lean mice using assay for transposase-accessible chromatin sequencing (ATAC-seq). We found that monocytes and ATMs from obese and lean mice exhibited distinct chromatin accessibility status. There are distinct regulatory elements that are specifically associated with monocyte or ATM activation in obesity. We also discovered several transcription factors that may regulate monocyte and ATM activation in obese mice, specifically a predicted transcription factor named ETS translocation variant 5 (ETV5). The expression of ETV5 was significantly decreased in ATMs from obese mice and its downregulation was mediated by palmitate stimulation. The decrease in ETV5 expression resulted in macrophage activation. Our results also indicate that ETV5 suppresses endoplasmic reticulum (ER) stress and Il6 expression in macrophages. Our work delineates the changes in chromatin accessibility in monocytes and ATMs during obesity, and identifies ETV5 as a critical transcription factor suppressing ATM activation, suggesting its potential use as a therapeutic target in obesity-related chronic inflammation.

摘要

脂肪组织巨噬细胞（ATMs）的激活会导致肥胖患者发生慢性炎症和胰岛素抵抗。然而，在肥胖的发展过程中，涉及 ATMs 激活的转录调控机制尚未完全阐明。在此，我们使用转座酶可及染色质测序（ATAC-seq）技术对肥胖和瘦小鼠的血液单核细胞和 ATMs 的染色质可及性进行了分析。结果发现，肥胖和瘦小鼠的单核细胞和 ATMs 表现出不同的染色质可及性状态。在肥胖中，存在与单核细胞或 ATMs 激活特异性相关的不同调节元件。我们还发现了几种可能调节肥胖小鼠单核细胞和 ATMs 激活的转录因子，特别是一个名为 ETS 易位变体 5（ETV5）的预测转录因子。肥胖小鼠的 ATMs 中 ETV5 的表达显著降低，其下调是由软脂酸刺激介导的。ETV5 表达的降低导致巨噬细胞的激活。我们的结果还表明，ETV5 抑制了巨噬细胞中的内质网（ER）应激和 Il6 表达。本研究描绘了肥胖过程中单核细胞和 ATMs 中染色质可及性的变化，并确定了 ETV5 作为抑制 ATMs 激活的关键转录因子，提示其可能作为肥胖相关慢性炎症的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/789d/8556336/658aa2b80a87/41419_2021_4308_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/789d/8556336/53e021bb7f1a/41419_2021_4308_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/789d/8556336/b6eb67b1ec71/41419_2021_4308_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/789d/8556336/bfbce70025e1/41419_2021_4308_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/789d/8556336/976ee4411512/41419_2021_4308_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/789d/8556336/658aa2b80a87/41419_2021_4308_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/789d/8556336/53e021bb7f1a/41419_2021_4308_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/789d/8556336/b6eb67b1ec71/41419_2021_4308_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/789d/8556336/bfbce70025e1/41419_2021_4308_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/789d/8556336/976ee4411512/41419_2021_4308_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/789d/8556336/658aa2b80a87/41419_2021_4308_Fig5_HTML.jpg

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