Laboratory of Molecular Genetics, Program in Genomics of Differentiation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
EMBO J. 2011 Jun 10;30(14):2894-907. doi: 10.1038/emboj.2011.184.
The caudal homeobox (cdx) gene family is critical for specification of caudal body formation and erythropoiesis. In zebrafish, cdx4 expression is controlled by the Wnt pathway, but the molecular mechanism of this regulation is not fully understood. Here, we provide evidence that Tcf3 suppresses cdx4 expression through direct binding to multiple sites in the cdx4 gene regulatory region. Tcf3 requires corepressor molecules such as Groucho (Gro)/TLE and HDAC1 for activity. Using zebrafish embryos and cultured mammalian cells, we show that the transcription factor E4f1 derepresses cdx4 by dissociating corepressor proteins from Tcf3 without inhibiting its binding to cis-regulatory sites in the DNA. Further, the E3 ubiquitin ligase Lnx2b, acting as a scaffold protein irrespective of its enzymatic activity, counteracts the effects of E4f1. We propose that the modulation of Tcf3 repressor function by E4f1 assures precise and robust regulation of cdx4 expression in the caudal domain of the embryo.
尾侧同源盒 (cdx) 基因家族对于尾部体形成和红细胞生成的特化至关重要。在斑马鱼中，cdx4 的表达受 Wnt 途径的控制，但这种调控的分子机制尚不完全清楚。在这里，我们提供的证据表明 Tcf3 通过直接结合 cdx4 基因调控区的多个位点来抑制 cdx4 的表达。Tcf3 需要 Groucho（Gro）/TLE 和组蛋白去乙酰化酶 1（HDAC1）等核心抑制分子来发挥活性。我们使用斑马鱼胚胎和培养的哺乳动物细胞表明，转录因子 E4f1 通过从 Tcf3 上解离核心抑制蛋白来解除对 cdx4 的抑制，而不抑制其与 DNA 中顺式调控位点的结合。此外，作为支架蛋白发挥作用的 E3 泛素连接酶 Lnx2b ，无论其酶活性如何，都能抵消 E4f1 的作用。我们提出，E4f1 对 Tcf3 抑制子功能的调节确保了胚胎尾部区域 cdx4 表达的精确和稳健调控。
