FOXC2 Autoregulates Its Expression in the Pulmonary Endothelium After Endotoxin Stimulation in a Histone Acetylation-Dependent Manner.
FOXC2 Autoregulates Its Expression in the Pulmonary Endothelium After Endotoxin Stimulation in a Histone Acetylation-Dependent Manner.
复制标题
FOXC2在内毒素刺激后以组蛋白乙酰化依赖的方式自动调节其在肺内皮细胞中的表达。
DOI：
10.3389/fcell.2021.657662
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发表时间：
2021
影响因子：
5.5
通讯作者：
Sampath V
中科院分区：
文献类型：
--
作者：
Xia S;Yu W;Menden H;Younger ST;Sampath V
肺内皮细胞（EC）对脂多糖（LPS）的先天免疫反应通过Toll样受体4 （TLR4）诱导叉头盒蛋白C2 （FOXC2）活化。在LPS刺激下，肺EC中FOXC2表达调控的机制尚不清楚。我们假设FOXC2在脓毒症中调节其自身表达，其转录自调节指导淋巴EC细胞命运的决定。生物信息学分析确定了FOXC2启动子中潜在的FOXC2结合位点。在人肺EC中，我们通过染色质免疫沉淀（ChIP）和荧光素酶检测证实FOXC2在LPS刺激后与自身启动子结合并刺激其表达。garcinol对组蛋白乙酰化的化学抑制抑制了lps诱导的FOXC2启动子区组蛋白乙酰化，并破坏了lps介导的FOXC2结合和转录激活。CRISPR/dCas9/gRNA靶向FOXC2结合元件（FBE），通过阻断FOXC2启动子中的FBEs，抑制lps刺激的FOXC2结合和自动调节，抑制淋巴EC标记物的表达。在无菌脓毒症的新生小鼠模型中，lps诱导的FOXC2与FBE的结合和FOXC2在肺EC中的表达在garcinol处理后减弱。这些数据揭示了lps诱导组蛋白乙酰化依赖性FOXC2自调节的新机制。
The innate immune response of pulmonary endothelial cells (EC) to lipopolysaccharide (LPS) induces Forkhead box protein C2 (FOXC2) activation through Toll Like Receptor 4 (TLR4). The mechanisms by which FOXC2 expression is regulated in lung EC under LPS stimulation remain unclear. We postulated that FOXC2 regulates its own expression in sepsis, and its transcriptional autoregulation directs lymphatic EC cell-fate decision. Bioinformatic analysis identified potential FOXC2 binding sites in the FOXC2 promoter. In human lung EC, we verified using chromatin immunoprecipitation (ChIP) and luciferase assays that FOXC2 bound to its own promoter and stimulated its expression after LPS stimulation. Chemical inhibition of histone acetylation by garcinol repressed LPS-induced histone acetylation in the FOXC2 promoter region, and disrupted LPS-mediated FOXC2 binding and transcriptional activation. CRISPR/dCas9/gRNA directed against FOXC2-binding-element (FBE) suppressed LPS-stimulated FOXC2 binding and autoregulation by blocking FBEs in the FOXC2 promoter, and repressed expression of lymphatic EC markers. In a neonatal mouse model of sterile sepsis, LPS-induced FOXC2 binding to FBE and FOXC2 expression in lung EC was attenuated with garcinol treatment. These data reveal a new mechanism of LPS-induced histone acetylation-dependent FOXC2 autoregulation.
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影响因子：
14.9
作者：
Josephs EA;Kocak DD;Fitzgibbon CJ;McMenemy J;Gersbach CA;Marszalek PE
通讯作者：
Marszalek PE
影响因子：
5.4
作者：
Fraineau, Sylvain;Palii, Carmen G.;Brand, Marjorie
通讯作者：
Brand, Marjorie
影响因子：
5.6
作者：
Kopytko P;Piotrowska K;Janisiak J;Tarnowski M
通讯作者：
Tarnowski M
FOXC2直接靶向MET促进结直肠癌转移
影响因子：
8
作者：
Cui, Y-M;Jiao, H-L;Ding, Y-Q
通讯作者：
Ding, Y-Q
影响因子：
4.6
作者：
Fish, Jason E.;Gutierrez, Manuel Cantu;Wythe, Joshua D.
通讯作者：
Wythe, Joshua D.