Department of Biological Sciences, KAIST, Daejeon 305-701, South Korea.
Mech Ageing Dev. 2011 Oct;132(10):511-4. doi: 10.1016/j.mad.2011.07.007. Epub 2011 Aug 9.
The canonical Wnt pathway plays a critical role in myogenesis and age-related inefficient muscle regeneration. To gain insights into changes in Wnt signaling in muscle during the lifetime of a mouse, mRNA levels of secreted Wnt antagonists were investigated. Among 13 analyzed antagonists, seven genes were found to be down-regulated in skeletal muscles of adult and old mice. Epigenetic modifications at the promoter regions of these seven Wnt antagonists were then examined to understand how these correlate with this transcriptional repression. DNA methylation was stably maintained, while chromatin modifications changed to transcriptionally inactive states over the course of a lifetime. Similar patterns of changes in chromatin modifications were observed at the promoters of all of the studied genes. The observations indicated that an upstream factor might regulate the chromatin states and the transcriptional repression of Wnt antagonists. Several bioinformatic analyses revealed that a FOXD3 binding motif is present within promoter regions of the seven antagonists. Furthermore, age-dependent differential FOXD3 binding is observed at the motifs of the seven gene promoters. Our results suggest that FOXD3 as a potential epigenetic regulator may mediate the transcriptional repression of the seven antagonists, possibly through regulation of histone modifications.
经典 Wnt 通路在肌发生和与年龄相关的肌肉再生效率低下中发挥着关键作用。为了深入了解小鼠一生中肌肉中 Wnt 信号的变化，研究了分泌型 Wnt 拮抗剂的 mRNA 水平。在分析的 13 种拮抗剂中，发现有 7 种基因在成年和老年小鼠的骨骼肌中下调。然后检查这些 7 种 Wnt 拮抗剂启动子区域的表观遗传修饰，以了解这些修饰与转录抑制的相关性。在整个生命周期中，DNA 甲基化保持稳定，而染色质修饰则转变为转录非活跃状态。在所有研究基因的启动子上都观察到了类似的染色质修饰变化模式。这些观察结果表明，上游因子可能调节 Wnt 拮抗剂的染色质状态和转录抑制。几项生物信息学分析表明，在 7 种拮抗剂的启动子区域内存在 FOXD3 结合基序。此外，在七个基因启动子的基序中观察到与年龄相关的 FOXD3 结合的差异。我们的研究结果表明，FOXD3 作为一种潜在的表观遗传调节剂，可能通过调节组蛋白修饰来介导这 7 种拮抗剂的转录抑制。
