FOXF1 transcription factor promotes lung regeneration after partial pneumonectomy.
FOXF1 transcription factor promotes lung regeneration after partial pneumonectomy.
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DOI：
10.1038/s41598-017-11175-3
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发表时间：
2017-09-06
影响因子：
4.6
通讯作者：
Kalinichenko VV
中科院分区：
文献类型：
--
作者：
Bolte C;Flood HM;Ren X;Jagannathan S;Barski A;Kalin TV;Kalinichenko VV
FOXF 1是叉头盒转录因子家族的成员，以前已被证明对肺发育、稳态和损伤反应至关重要。然而，FOXF 1在肺再生中的作用尚不清楚。在此，我们在内皮细胞中缺乏一个Foxf 1等位基因的小鼠（PDGFb-iCre/Foxf 1 fl/+小鼠）中进行了部分肺切除术，这是一种肺再生模型。内皮细胞增殖显着减少再生肺从小鼠缺乏内皮Foxf 1。内皮细胞增殖减少与延迟肺再生相关，如Foxf 1缺陷肺中呼吸量减少所示。将从再生的PDGFb-iCre/Foxfl fl/+和对照肺分离的FACS分选的内皮细胞用于RNAseq分析以鉴定FOXFl靶基因。Foxf 1缺陷改变了许多基因的表达，包括调节细胞外基质重塑（Timp 3，Adamts 9）和细胞周期进程（Cdkn 1a，Cdkn 2b，Cenpj，Tubb 4a）的基因，这些基因对肺再生至关重要。Foxf 1的缺失增加了Timp 3的mRNA和蛋白，降低了再生肺中MMP 14的活性。针对FOXF 1和组蛋白甲基化标记的ChIPseq分析鉴定了Cd 44、Cdkn 1a和Cdkn 2b基因内的DNA调控区域，表明它们是FOXF 1的直接靶点。因此，FOXF 1通过直接转录调节细胞外基质重塑和细胞周期进展的关键基因来刺激部分肺切除术后的肺再生。
FOXF1, a member of the forkhead box family of transcription factors, has been previously shown to be critical for lung development, homeostasis, and injury responses. However, the role of FOXF1 in lung regeneration is unknown. Herein, we performed partial pneumonectomy, a model of lung regeneration, in mice lacking one Foxf1 allele in endothelial cells (PDGFb-iCre/Foxf1 fl/+ mice). Endothelial cell proliferation was significantly reduced in regenerating lungs from mice deficient for endothelial Foxf1. Decreased endothelial proliferation was associated with delayed lung regeneration as shown by reduced respiratory volume in Foxf1-deficient lungs. FACS-sorted endothelial cells isolated from regenerating PDGFb-iCre/Foxf1 fl/+ and control lungs were used for RNAseq analysis to identify FOXF1 target genes. Foxf1 deficiency altered expression of numerous genes including those regulating extracellular matrix remodeling (Timp3, Adamts9) and cell cycle progression (Cdkn1a, Cdkn2b, Cenpj, Tubb4a), which are critical for lung regeneration. Deletion of Foxf1 increased Timp3 mRNA and protein, decreasing MMP14 activity in regenerating lungs. ChIPseq analysis for FOXF1 and histone methylation marks identified DNA regulatory regions within the Cd44, Cdkn1a, and Cdkn2b genes, indicating they are direct FOXF1 targets. Thus FOXF1 stimulates lung regeneration following partial pneumonectomy via direct transcriptional regulation of genes critical for extracellular matrix remodeling and cell cycle progression.
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影响因子：
3.7
作者：
Bolte C;Zhang Y;Wang IC;Kalin TV;Molkentin JD;Kalinichenko VV
通讯作者：
Kalinichenko VV
影响因子：
5.6
作者：
Akram KM;Patel N;Spiteri MA;Forsyth NR
通讯作者：
Forsyth NR
影响因子：
7.3
作者：
Cai, Yuqi;Bolte, Craig;Kalinichenko, Vladimir V.
通讯作者：
Kalinichenko, Vladimir V.
影响因子：
1.2
作者：
Kalinichenko, VV;Gusarova, GA;Costa, RH
通讯作者：
Costa, RH
影响因子：
14.9
作者：
Chen J;Bardes EE;Aronow BJ;Jegga AG
通讯作者：
Jegga AG