Fibroblast growth factor maintains chondrogenic potential of limb bud mesenchymal cells by modulating DNMT3A recruitment.
Fibroblast growth factor maintains chondrogenic potential of limb bud mesenchymal cells by modulating DNMT3A recruitment.
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DOI：
10.1016/j.celrep.2014.07.038
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发表时间：
2014-09-11
期刊：
影响因子：
8.8
通讯作者：
Lassar AB
中科院分区：
文献类型：
--
作者：
Kumar D;Lassar AB
软骨的形成被外胚层Wnt限制在肢芽间充质的核心，其可以不可逆地沉默软骨形成转录因子Sox 9的表达。相反，来自顶端外胚层嵴的成纤维细胞生长因子（FGF）信号维持软骨形成前体的能力，一旦这些细胞超出外胚层Wnt信号的范围，则进行软骨形成。我们已经发现，Wnt信号诱导抑制性染色质标记（H3 K27 me 3）和DNA甲基化的Sox 9启动子和Wnt诱导的不可逆沉默的Sox 9基因需要这个位点的DNA甲基化，这是特别的FGF信号抵消。FGF通过诱导DNMT 3A与ERK 1/2的相互作用和磷酸化，阻断从头DNA甲基转移酶DNMT 3A向Sox 9启动子的募集，从而控制Sox 9的表达是否被肢芽间充质细胞中的Wnt信号不可逆或可逆地沉默。
The formation of cartilage is restricted to the core of the limb bud mesenchyme by ectodermal Wnts, which can irreversibly silence expression of the prochondrogenic transcription factor Sox9. In contrast, fibroblast growth factor (FGF) signals from the apical ectodermal ridge maintain the competence of chondrogenic precursors to undergo chondrogenesis once these cells go out of range of ectodermal Wnt signals. We have found that Wnt signals induce both a repressive chromatin mark (H3K27me3) and DNA methylation over the Sox9 promoter and that Wnt-induced irreversible silencing of the Sox9 gene requires DNA methylation of this locus, which is specifically countered by FGF signals. FGF blocks the recruitment of the de novo DNA methyltransferase, DNMT3A, to the Sox9 promoter by inducing the interaction and phosphorylation of DNMT3A by ERK1/2, and thereby controls whether expression of Sox9 is either irreversibly or reversibly silenced by Wnt signals in limb bud mesenchymal cells.
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