JmjC Domain-containing Protein 6 (Jmjd6) Derepresses the Transcriptional Repressor Transcription Factor 7-like 1 (Tcf7l1) and Is Required for Body Axis Patterning during Xenopus Embryogenesis*
JmjC Domain-containing Protein 6 (Jmjd6) Derepresses the Transcriptional Repressor Transcription Factor 7-like 1 (Tcf7l1) and Is Required for Body Axis Patterning during Xenopus Embryogenesis*
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DOI：
10.1074/jbc.m115.646554
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发表时间：
2015-07
期刊：
影响因子：
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通讯作者：
Xuena Zhang;Yan Gao;Lei Lu;Zan Zhang;Shengchun Gan;Liyang Xu;A. Lei;Ying Cao
中科院分区：
文献类型：
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作者：
Xuena Zhang;Yan Gao;Lei Lu;Zan Zhang;Shengchun Gan;Liyang Xu;A. Lei;Ying Cao
背景：Tcf 7 l1的阻遏活性是如何调节的还不清楚。结果：Jmjd 6与Tcf 71结合并解抑制Tcf 71。结论：Jmjd 6在Tcf 7 l1去阻遏和爪蟾体轴模式形成中起重要作用。重要性：Jmjd 6对Tcf 7 l1的去抑制是一种新的机制，不仅可以理解胚胎中的Wnt作用，还可以理解干细胞和癌症中的Wnt作用。Tcf 7 l1（也称为Tcf 3）是一种双峰转录因子，在胚胎发生以及胚胎和成体干细胞中发挥重要作用。Tcf 7 l1一方面通过募集Groucho相关的转录辅抑制因子来抑制Wnt靶基因的转录，另一方面通过与Wnt激活的β-catenin相互作用来激活Wnt靶基因，但其作用机制尚不清楚。在这里，我们表明，JmjC结构域包含的蛋白质，Jmjd 6，与Tcf 7 l相互作用和解阻遏Tcf 7 l。我们发现，Jmjd 6结合到Tcf 7 l1的一个区域，也是负责Groucho相互作用，因此有可能Jmjd 6结合取代从Tcf 7 l1的Groucho转录辅阻遏物。此外，我们发现，Jmjd 6拮抗Tcf 7 l1对靶基因转录的抑制作用，并能够增强β-连环蛋白诱导的基因激活，反之亦然，抑制Jmjd 6活性会损害细胞和爪蟾早期胚胎中的基因激活。我们还表明，jmjd 6是母系和合子在非洲爪蟾胚胎发生转录。Jmjd 6功能的丧失会导致前后体轴形成缺陷以及参与前后体轴模式的基因下调。结果阐明了一种新的机制，潜在的Tcf 7 l1活性的调节和胚胎体轴形成的调节。
Background: How the repression activity of Tcf7l1 is regulated is not well understood. Results: Jmjd6 binds to and derepresses Tcf71. Conclusion: Jmjd6 is essential for derepression of Tcf7l1 and Xenopus body axis patterning. Significance: Derepression of Tcf7l1 by Jmjd6 is a novel mechanism for the understanding of Wnt action in not only embryos but also in stem cells and cancers. Tcf7l1 (also known as Tcf3) is a bimodal transcription factor that plays essential roles in embryogenesis and embryonic and adult stem cells. On one hand, Tcf7l1 works as transcriptional repressor via the recruitment of Groucho-related transcriptional corepressors to repress the transcription of Wnt target genes, and, on the other hand, it activates Wnt target genes when Wnt-activated β-catenin interacts with it. However, how its activity is modulated is not well understood. Here we demonstrate that a JmjC-domain containing protein, Jmjd6, interacts with Tcf7l and derepresses Tcf7l. We show that Jmjd6 binds to a region of Tcf7l1 that is also responsible for Groucho interaction, therefore making it possible that Jmjd6 binding displaces the Groucho transcriptional corepressor from Tcf7l1. Moreover, we show that Jmjd6 antagonizes the repression effect of Tcf7l1 on target gene transcription and is able to enhance β-catenin-induced gene activation and that, vice versa, inhibition of Jmjd6 activity compromises gene activation in both cells and Xenopus early embryos. We also show that jmjd6 is both maternally and zygotically transcribed during Xenopus embryogenesis. Loss of Jmjd6 function causes defects in anterioposterior body axis formation and down-regulation of genes that are involved in anterioposterior axis patterning. The results elucidate a novel mechanism underlying the regulation of Tcf7l1 activity and the regulation of embryonic body axis formation.