FGF-induced Pea3 transcription factors program the genetic landscape for cell fate determination.
FGF-induced Pea3 transcription factors program the genetic landscape for cell fate determination.
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DOI：
10.1371/journal.pgen.1007660
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发表时间：
2018-09
期刊：
影响因子：
4.5
通讯作者：
Zhang X
中科院分区：
文献类型：
--
作者：
Garg A;Hannan A;Wang Q;Collins T;Teng S;Bansal M;Zhong J;Xu K;Zhang X
FGF信号是眼内泪腺发育的有效诱导剂，能够将角膜上皮转化为腺组织。在这里，我们发现Pea3家族转录因子的基因消融不仅破坏了泪腺的导管延伸和分支，而且使泪腺上皮细胞倾向于表皮细胞的命运。高通量基因表达分析和染色质免疫沉淀数据显示，Pea3基因直接控制FGF信号的正负反馈回路。重要的是，Pea3基因也需要抑制异常的Notch信号，如果不加以控制，可以通过阻止Sox和Six家族基因的表达来损害泪腺的发育。这些结果表明，Pea3基因是FGF早期反应的关键转录因子，为细胞命运的决定编程遗传景观。FGF信号通过诱导基因表达的全基因组变化来调节细胞命运的决定。我们发现Pea3家族转录因子是FGF信号重编程上皮转录组的关键效应因子。Pea3因子控制泪腺发育过程中FGF信号的反馈和前馈回路。它们还激活Six和Sox家族基因的特异性表达，抑制Notch信号的异常激活。在Pea3基因缺失的情况下，泪腺祖细胞的基因表达模式变成表皮样。Pea3功能的研究解决了FGF如何诱导泪腺命运的长期难题，为泪腺再生治疗干眼病提供了方向。
FGF signaling is a potent inducer of lacrimal gland development in the eye, capable of transforming the corneal epithelium into glandular tissues. Here, we show that genetic ablation of the Pea3 family of transcription factors not only disrupted the ductal elongation and branching of the lacrimal gland, but also biased the lacrimal gland epithelium toward an epidermal cell fate. Analysis of high-throughput gene expression and chromatin immunoprecipitation data revealed that the Pea3 genes directly control both the positive and negative feedback loops of FGF signaling. Importantly, Pea3 genes are also required to suppress aberrant Notch signaling which, if gone unchecked, can compromise lacrimal gland development by preventing the expression of both Sox and Six family genes. These results demonstrate that Pea3 genes are key FGF early response transcriptional factors, programing the genetic landscape for cell fate determination. FGF signaling regulates cell fate decision by inducing genome-wide changes in gene expression. We identified Pea3 family transcription factors as the key effectors of FGF signaling in reprograming the epithelia transcriptome. Pea3 factors control both the feedback and feedforward circuities of FGF signaling in lacrimal gland development. They also activate specific expression of Six and Sox family genes and suppress aberrant activation of Notch signaling. In the absence of Pea3 genes, the lacrimal gland progenitors become epidermal-like in their gene expression patterns. The study of Pea3 function resolves the long standing conundrum of how FGF induces the lacrimal gland fate, providing direction for regenerating the lacrimal gland to treat dry eye diseases.
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