L-Sox5 and Sox6 drive expression of the aggrecan gene in cartilage by securing binding of Sox9 to a far-upstream enhancer
L-Sox5 and Sox6 drive expression of the aggrecan gene in cartilage by securing binding of Sox9 to a far-upstream enhancer
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DOI：
10.1128/mcb.00695-08
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发表时间：
2008-08-01
影响因子：
5.3
通讯作者：
Lefebvre, Veronique
中科院分区：
文献类型：
--
作者：
Han, Yu;Lefebvre, Veronique
Sry相关的高迁移率族盒转录因子Sox9募集冗余的L - Sox5和Sox6蛋白以影响软骨形成，但这三者的作用模式仍不清楚。我们在此鉴定出聚集蛋白聚糖（一种对软骨至关重要的蛋白聚糖以及软骨细胞分化的关键标志物）的Age1基因上游10kb处一个高度保守的359bp序列。该序列在转基因小鼠的胚胎和成年软骨中指导一个最小启动子的表达，其方式与Age1的表达相匹配。软骨形成相关的这三个因子是介导此增强子活性所必需且足够的。它直接起作用，Sox9结合一个关键的顺式作用元件，L - Sox5/Sox6结合另外三个元件，这三个元件是协同需要的。在结合到它们的特异性位点后，L - Sox5/Sox6提高了Sox9结合其自身识别位点的效率，从而有力地增强了Sox9激活增强子的能力。L - Sox5/Sox6同样确保Sox9结合到C612a1（编码胶原蛋白 - 2）和其他软骨特异性增强子上。因此，这项研究揭示了驱动Age1在软骨中表达的关键顺式作用元件和转录因子，并增进了对软骨形成相关Sox三因子作用模式的理解。
The Sry-related high-mobility-group box transcription factor Sox9 recruits the redundant L-Sox5 and Sox6 proteins to effect chondrogenesis, but the mode of action of the trio remains unclear. We identify here a highly conserved 359-bp sequence 10 kb upstream of the Age1 gene for aggrecan, a most essential cartilage proteoglycan and key marker of chondrocyte differentiation. This sequence directs expression of a minimal promoter in both embryonic and adult cartilage in transgenic mice, in a manner that matches Age1 expression. The chondrogenic trio is required and sufficient to mediate the activity of this enhancer. It acts directly, Sox9 binding to a critical cis-acting element and L-Sox5/Sox6 binding to three additional elements, which are cooperatively needed. Upon binding to their specific sites, L-Sox5/Sox6 increases the efficiency of Sox9 binding to its own recognition site and thereby robustly potentiates the ability of Sox9 to activate the enhancer. L-Sox5/Sox6 similarly secures Sox9 binding to C612a1 (encoding collagen-2) and other cartilage-specific enhancers. This study thus uncovers critical cis-acting elements and transcription factors driving Age1 expression in cartilage and increases understanding of the mode of action of the chondrogenic Sox trio.