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包含成簇的GATA2结合位点和PU.1结合位点的-39 kb增强子对于在小鼠肥大细胞中的表达至关重要。

The -39 kb enhancer containing clustered GATA2- and PU.1-binding sites is essential for expression in murine mast cells.

作者信息

Ohmori Shin'ya, Takai Jun, Uemura Satoshi, Otsuki Akihito, Mori Tetsuya, Ohneda Kinuko, Moriguchi Takashi

机构信息

Department of Pharmacy, Faculty of Pharmacy, Takasaki University of Health and Welfare, Takasaki, Japan.

Division of Medical Biochemistry, Tohoku Medical Pharmaceutical University, Sendai, Japan.

出版信息

iScience. 2022 Aug 14;25(9):104942. doi: 10.1016/j.isci.2022.104942. eCollection 2022 Sep 16.

DOI:10.1016/j.isci.2022.104942
PMID:36072552
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9442365/
Abstract

Mast cells serve as a first-line defense of innate immunity. Interleukin-6 (IL-6) induced by bacterial lipopolysaccharide (LPS) in mast cells plays a crucial role in antibacterial protection. The zinc finger transcription factor GATA2 cooperatively functions with the ETS family transcription factor PU.1 in multiple mast cell activities. However, the regulatory landscape directed by GATA2 and PU.1 under inflammation remains elusive. We herein showed that a large proportion of GATA2-binding peaks were closely located with PU.1-binding peaks in distal -regulatory regions of inflammatory cytokine genes in mast cells. Notably, GATA2 and PU.1 played crucial roles in promoting LPS-mediated inflammatory cytokine production. Genetic ablation of GATA2-PU.1-clustered binding sites at the -39 kb region revealed its central role in LPS-induced expression in mast cells. We demonstrate a novel collaborative activity of GATA2 and PU.1 in cytokine induction upon inflammatory stimuli via the GATA2-PU.1 overlapping sites in the distal -regulatory regions.

摘要

肥大细胞是固有免疫的一线防御细胞。细菌脂多糖（LPS）诱导肥大细胞产生的白细胞介素-6（IL-6）在抗菌保护中起关键作用。锌指转录因子GATA2与ETS家族转录因子PU.1在多种肥大细胞活动中协同发挥作用。然而，在炎症状态下由GATA2和PU.1调控的情况仍不清楚。我们在此表明，在肥大细胞炎症细胞因子基因的远端调控区域，很大一部分GATA2结合峰与PU.1结合峰紧密相邻。值得注意的是，GATA2和PU.1在促进LPS介导的炎症细胞因子产生中起关键作用。在 -39 kb区域对GATA2-PU.1聚集结合位点进行基因敲除，揭示了其在肥大细胞中LPS诱导 表达中的核心作用。我们证明了GATA2和PU.1通过远端调控区域的GATA2-PU.1重叠位点在炎症刺激下细胞因子诱导中具有新的协同活性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b9c5/9442365/a2f13618dab8/gr8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b9c5/9442365/e07d0713396d/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b9c5/9442365/d4f03e206ad7/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b9c5/9442365/baee34447044/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b9c5/9442365/c630b4fd798c/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b9c5/9442365/4ffe8d22d24e/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b9c5/9442365/328eec662086/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b9c5/9442365/9ce8bd42d5a8/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b9c5/9442365/0f023721b009/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b9c5/9442365/a2f13618dab8/gr8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b9c5/9442365/e07d0713396d/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b9c5/9442365/d4f03e206ad7/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b9c5/9442365/baee34447044/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b9c5/9442365/c630b4fd798c/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b9c5/9442365/4ffe8d22d24e/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b9c5/9442365/328eec662086/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b9c5/9442365/9ce8bd42d5a8/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b9c5/9442365/0f023721b009/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b9c5/9442365/a2f13618dab8/gr8.jpg

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