HOXA10 controls osteoblastogenesis by directly activating bone regulatory and phenotypic genes
HOXA10 controls osteoblastogenesis by directly activating bone regulatory and phenotypic genes
复制标题
DOI：
10.1128/mcb.01544-06
复制
发表时间：
2007-05-01
影响因子：
5.3
通讯作者：
Lian, Jane B.
中科院分区：
文献类型：
--
作者：
Hassan, Mohammad Q.;Tare, Rahul;Lian, Jane B.
HOXA10 对于骨骼元素的胚胎模式是必需的，但其在早期发育阶段之后的骨形成中的功能尚不清楚。在这里，我们表明 HOXA10 通过激活 Runx2 有助于成骨谱系决定，并直接调节成骨细胞表型基因。响应骨形态发生蛋白 BMP2，Hoxa10 被快速诱导并发挥作用，激活骨形成所必需的 Runx2 转录因子。具有 Hox 核心基序的功能元件被表征为骨相关 Runx2 P1 启动子。 HOXA10 还激活其他成骨基因，包括碱性磷酸酶、骨钙素和骨唾液蛋白基因，并在招募 RUNX2 之前的成骨细胞分化阶段暂时与这些靶基因启动子相关。外源表达和小干扰 RNA 敲低研究表明，HOXA10 介导这些基因的染色质高度乙酰化和三甲基组蛋白 K4 (H3K4) 甲基化，与活性转录相关。因此，HOXA10 通过染色质重塑有助于成骨基因的早期表达。重要的是，HOXA10可以在Runx2无效细胞中诱导成骨细胞基因，这为不依赖于RUNX2的介导成骨细胞分化的直接作用提供了证据。我们提出HOXA10激活间充质细胞中的RUNX2，促进成骨的开始，并且HOXA10随后通过直接调节成骨细胞表型基因来支持骨形成。
HOXA10 is necessary for embryonic patterning of skeletal elements, but its function in bone formation beyond this early developmental stage is unknown. Here we show that HOXA10 contributes to osteogenic lineage determination through activation of Runx2 and directly regulates osteoblastic phenotypic genes. In response to bone morphogenic protein BMP2, Hoxa10 is rapidly induced and functions to activate the Runx2 transcription factor essential for bone formation. A functional element with the Hox core motif was characterized for the bone-related Runx2 P1 promoter. HOXA10 also activates other osteogenic genes, including the alkaline phosphatase, osteocalcin, and bone sialoprotein genes, and temporally associates with these target gene promoters during stages of osteoblast differentiation prior to the recruitment of RUNX2. Exogenous expression and small interfering RNA knockdown studies establish that HOXA10 mediates chromatin hyperacetylation and trimethyl histone K4 (H3K4) methylation of these genes, correlating to active transcription. HOXA10 therefore contributes to early expression of osteogenic genes through chromatin remodeling. Importantly, HOXA10 can induce osteoblast genes in Runx2 null cells, providing evidence for a direct role in mediating osteoblast differentiation independent of RUNX2. We propose that HOXA10 activates RUNX2 in mesenchymal cells, contributing to the onset of osteogenesis, and that HOXA10 subsequently supports bone formation by direct regulation of osteoblast phenotypic genes.