小鼠巨噬细胞中指导 Il6 转录的推定增强子区域的鉴定和特征描述

IF 4.8 4区 医学 Q2 IMMUNOLOGY International immunology Pub Date : 2024-08-13 DOI:10.1093/intimm/dxae024
Norisuke Kano, Takeo Miki, Yurina Uehara, Daisuke Ori, Taro Kawai
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引用次数: 0

摘要

白细胞介素-6(IL-6)在包括先天性和适应性免疫反应在内的各种细胞功能中发挥着至关重要的作用。IL-6表达失调与炎症亢进和慢性炎症性疾病有关。在这项研究中,我们旨在确定小鼠巨噬细胞中负责Il6 mRNA强表达的增强子区域。通过全面的全基因组 ChIP-seq 和 ATAC-seq 分析,我们在脂多糖(LPS)激活的小鼠巨噬细胞中发现了两个不同的簇,称为 E1 和 E2 区,分别位于 Il6 转录起始位点的 -144 kb 至 -163 kb 处。这些集群显示出组蛋白修饰标记(H3K27ac 和 H3K4me1)的积累以及染色质的开放,并发现它们包含转录因子 PU.1、NF-κB、C/EBPβ 和 JunB 的结合位点。在 LPS 刺激下,观察到来自 E1 和 E2 区域的非编码 RNA(ncRNA)转录本上调,这些 ncRNA 的抑制导致 Il6 表达减弱。此外,E1 或 E2 区域的缺失会显著影响 Il6 的表达,而 CRISPR/dCas9 激活介导的共激活剂 p300 招募到 E1 和 E2 区域会促进 Il6 的表达。总之,我们的研究结果表明,E1和E2区是Il6表达的假定增强子。
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Identification and characterization of putative enhancer regions that direct Il6 transcription in murine macrophages.

Interleukin-6 (IL-6) plays a crucial role in various cellular functions, including innate and adaptive immune responses. Dysregulated expression of IL-6 is associated with hyperinflammation and chronic inflammatory diseases. In this study, we aimed to identify the enhancer regions responsible for robust Il6 mRNA expression in murine macrophages. Through comprehensive genome-wide ChIP- and ATAC-seq analyses, we identified two distinct clusters, termed E1 and E2 regions, located at -144 to -163 kb relative to the Il6 transcription start site in lipopolysaccharide (LPS)-activated murine macrophages. These clusters exhibited an accumulation of histone modification marks (H3K27ac and H3K4me1), as well as open chromatin, and were found to contain binding sites for the transcription factors PU.1, NF-κB, C/EBPβ, and JunB. Upregulation of non-coding RNA (ncRNA) transcripts from the E1 and E2 regions was observed upon LPS stimulation, and repression of these ncRNAs resulted in abrogation of Il6 expression. Additionally, deletion of either E1 or E2 region significantly impaired Il6 expression, while CRISPR/dCas9 activation-mediated recruitment of the co-activator p300 to the E1 and E2 regions facilitated Il6 expression. Collectively, our findings suggest that the E1 and E2 regions serve as putative enhancers for Il6 expression.

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来源期刊
International immunology
International immunology 医学-免疫学
CiteScore
9.30
自引率
2.30%
发文量
51
审稿时长
6-12 weeks
期刊介绍: International Immunology is an online only (from Jan 2018) journal that publishes basic research and clinical studies from all areas of immunology and includes research conducted in laboratories throughout the world.
期刊最新文献
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