Phosphorylation Regulates FOXC2-Mediated Transcription in Lymphatic Endothelial Cells
Phosphorylation Regulates FOXC2-Mediated Transcription in Lymphatic Endothelial Cells
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DOI：
10.1128/mcb.01387-12
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发表时间：
2013-10-01
影响因子：
5.3
通讯作者：
Petrova, Tatiana V.
中科院分区：
文献类型：
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作者：
Ivanov, Konstantin I.;Agalarov, Yan;Petrova, Tatiana V.
连接细胞信号和基因表达调控的关键机制之一是转录因子的可逆磷酸化。FOXC2是一种叉头转录因子，在人类血管疾病淋巴水肿-二叉症中发生突变，在淋巴管发育中发挥重要作用。然而，调控FOXC2转录活性的机制尚不清楚。我们在这里报道了FOXC2在八个进化上保守的丝氨酸/苏氨酸残基上被磷酸化。这些位点的磷酸化缺失会引发FOXC2转录程序的实质性变化。通过对淋巴管内皮细胞的全基因组定位分析，我们证明这些变化是由于FOXC2对染色质募集的选择性抑制。不同结合部位的抑制程度不同，提示了一种新的变阻器机制，通过这种机制，FOXC2磷酸化可以差异地调节特定基因的表达。此外，与野生型蛋白不同，FOXC2的磷酸化缺陷突变体在体内不能诱导血管重构。总之，我们的结果指出了磷酸化在调节FOXC2介导的淋巴管内皮细胞转录中的关键作用，并强调了FOXC2磷酸化在血管发育中的重要性。
One of the key mechanisms linking cell signaling and control of gene expression is reversible phosphorylation of transcription factors. FOXC2 is a forkhead transcription factor that is mutated in the human vascular disease lymphedema-distichiasis and plays an essential role in lymphatic vascular development. However, the mechanisms regulating FOXC2 transcriptional activity are not well understood. We report here that FOXC2 is phosphorylated on eight evolutionarily conserved proline-directed serine/threonine residues. Loss of phosphorylation at these sites triggers substantial changes in the FOXC2 transcriptional program. Through genome-wide location analysis in lymphatic endothelial cells, we demonstrate that the changes are due to selective inhibition of FOXC2 recruitment to chromatin. The extent of the inhibition varied between individual binding sites, suggesting a novel rheostat-like mechanism by which expression of specific genes can be differentially regulated by FOXC2 phosphorylation. Furthermore, unlike the wild-type protein, the phosphorylation-deficient mutant of FOXC2 failed to induce vascular remodeling in vivo. Collectively, our results point to the pivotal role of phosphorylation in the regulation of FOXC2-mediated transcription in lymphatic endothelial cells and underscore the importance of FOXC2 phosphorylation in vascular development.