Epigenetic Regulation of Early Osteogenesis and Mineralized Tissue Formation by a HOXA10-PBX1-Associated Complex
Epigenetic Regulation of Early Osteogenesis and Mineralized Tissue Formation by a HOXA10-PBX1-Associated Complex
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DOI：
10.1159/000324790
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发表时间：
2011-01-01
影响因子：
2.7
通讯作者：
Lian, Jane B.
中科院分区：
文献类型：
--
作者：
Gordon, Jonathan A. R.;Hassan, Mohammad Q.;Lian, Jane B.
含同源结构域（HOX）因子，如腹部类同源结构域蛋白HOXA 10和TALE家族蛋白PBX 1形成共调节复合物，是组织形态发生的有效转录和表观遗传调节因子。我们已经确定HOXA 10和PBX 1在骨祖细胞中表达;然而，它们在骨生成中的作用尚未确定。为了确定HOXA 10-PBX介导的成骨细胞定型和相关基因表达的调节机制，在C3 H10 T1/2、骨髓基质祖细胞和MC 3 T3-E1（前成骨细胞）细胞中耗尽（分别为shRNA或基因缺失）或外源性表达PBX 1或HOX 10。HOXA 10的过表达增加了成骨细胞相关基因的表达、成骨细胞的分化和矿化; PBX 1的表达损害了多能细胞的成骨承诺和成骨细胞的分化。相比之下，通过shRNA靶向消耗PBX 1增加了骨标记基因（osterix，碱性磷酸酶，BSP和骨钙素）的表达。染色质相关的PBX 1和HOXA 10存在于成骨细胞相关基因启动子的基因表达之前，但PBX 1在骨相关基因，包括osterix（Osx）的转录过程中不存在。此外，PBX 1复合物与通常与染色质失活相关的组蛋白脱乙酰酶相关。Osx启动子中PBX 1的缺失而不是HOXA 10的缺失与组蛋白乙酰化酶（p300）募集的增加以及H3 K9甲基化的减少有关，反映了转录激活。我们建议PBX 1在减弱HOXA 10作为成骨细胞相关基因的激活剂的活性中发挥核心作用，并在骨生成过程中建立适当的基因表达时机，从而导致分化的成骨细胞中适当的基质成熟和矿物质沉积。版权所有（C）2011 S. Karger AG，巴塞尔
Homeodomain-containing (HOX) factors such as the abdominal class homeodomain protein HOXA10 and the TALE-family protein PBX1 form coregulatory complexes and are potent transcriptional and epigenetic regulators of tissue morphogenesis. We have identified that HOXA10 and PBX1 are expressed in osteoprogenitors; however, their role in osteogenesis has not been established. To determine the mechanism of HOXA10-PBX-mediated regulation of osteoblast commitment and the related gene expression, PBX1 or HOX10 were depleted (shRNA or genetic deletion, respectively) or exogenously expressed in C3H10T1/2, bone marrow stromal progenitors, and MC3T3-E1 (preosteoblast) cells. Overexpression of HOXA10 increased the expression of osteoblast-related genes, osteoblast differentiation and mineralization; expression of PBX1 impaired osteogenic commitment of pluripotent cells and the differentiation of osteoblasts. In contrast, the targeted depletion of PBX1 by shRNA increased the expression of bone marker genes (osterix, alkaline phosphatase, BSP, and osteocalcin). Chromatin-associated PBX1 and HOXA10 were present at osteoblast-related gene promoters preceding gene expression, but PBX1 was absent from promoters during the transcription of bone-related genes, including osterix (Osx). Further, PBX1 complexes were associated with histone deacetylases normally linked with chromatin inactivation. Loss of PBX1 but not of HOXA10 from the Osx promoter was associated with increases in the recruitment of histone acetylases (p300), as well as decreased H3K9 methylation, reflecting transcriptional activation. We propose PBX1 plays a central role in at tenuating the activity of HOXA10 as an activator of osteoblast-related genes and functions to establish the proper timing of gene expression during osteogenesis, resulting in proper matrix maturation and mineral deposition in differentiated osteoblasts. Copyright (C) 2011 S. Karger AG, Basel