SOX9 is dispensable for the initiation of epigenetic remodeling and the activation of marker genes at the onset of chondrogenesis
SOX9 is dispensable for the initiation of epigenetic remodeling and the activation of marker genes at the onset of chondrogenesis
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DOI：
10.1242/dev.164459
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发表时间：
2018-07-15
期刊：
影响因子：
4.6
通讯作者：
Lefebvre, Veronique
中科院分区：
文献类型：
--
作者：
Liu, Chia-Feng;Angelozzi, Marco;Lefebvre, Veronique
SOX 9在主要生物过程中控制细胞谱系命运和分化。它被认为是分化特异性基因的有效转录激活因子，但其最早的靶点及其对启动染色质进行基因激活的贡献仍然未知。在这里，我们使用软骨形成作为模型系统来解决这一知识缺口。通过分析野生型和Sox 9缺陷小鼠胚胎肢芽的整个转录组和整个表观基因组，我们发现了多个结构和调节基因，包括Fam 101 a、Myh 14、Sema 3c和Sema 3d，作为软骨前浓缩的特异性标志物，并且我们提供了它们被SOX 9直接反式激活的证据。有趣的是，我们发现SOX 9有助于消除转录抑制的表观遗传特征，并在前软骨和软骨特异性位点建立活性启动子和活性增强子标记，但并不是启动这些变化和激活转录所必需的。总之，这些发现拓宽了我们目前对早期软骨形成中SOX 9靶点的了解，并呼吁进行新的研究，以确定在SOX 9上游或沿着作用的先锋和反式激活因子，以促进软骨形成和其他过程开始时的染色质重塑和特异性基因激活。
SOX9 controls cell lineage fate and differentiation in major biological processes. It is known as a potent transcriptional activator of differentiation-specific genes, but its earliest targets and its contribution to priming chromatin for gene activation remain unknown. Here, we address this knowledge gap using chondrogenesis as a model system. By profiling the whole transcriptome and the whole epigenome of wild-type and Sox9-deficient mouse embryo limb buds, we uncover multiple structural and regulatory genes, including Fam101a, Myh14, Sema3c and Sema3d, as specific markers of precartilaginous condensation, and we provide evidence of their direct transactivation by SOX9. Intriguingly, we find that SOX9 helps remove epigenetic signatures of transcriptional repression and establish active-promoter and active-enhancer marks at precartilage-and cartilage-specific loci, but is not absolutely required to initiate these changes and activate transcription. Altogether, these findings widen our current knowledge of SOX9 targets in early chondrogenesis and call for new studies to identify the pioneer and transactivating factors that act upstream of or along with SOX9 to prompt chromatin remodeling and specific gene activation at the onset of chondrogenesis and other processes.