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Epigenetic Regulation of Early Osteogenesis and Mineralized Tissue Formation by a HOXA10-PBX1-Associated Complex

机译：HOXA10-PBX1相关复合物早期成骨和矿化组织形成的表观遗传调控。

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摘要

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 attenuating 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.
机译：含Homeodomain的（HOX）因子（如腹部类Homeodomain蛋白HOXA10和TALE-家族蛋白PBX1）形成可调节复合物，并且是组织形态发生的有效转录和表观遗传调控因子。我们已经确定HOXA10和PBX1在骨祖细胞中表达。然而，它们在成骨中的作用尚未确定。为了确定HOXA10-PBX介导的成骨细胞定向调控和相关基因表达的机制，将PBX1或HOX10耗尽（分别为shRNA或遗传缺失）或在C3H10T1 / 2，骨髓基质祖细胞和MC3T3-E1中外源表达（成骨细胞）细胞。 HOXA10的过表达增加成骨细胞相关基因的表达，成骨细胞分化和矿化； PBX1的表达会损害多能细胞的成骨作用以及成骨细胞的分化。相反，shRNA靶向清除PBX1会增加骨标志物基因（osterix，碱性磷酸酶，BSP和骨钙蛋白）的表达。染色质相关的PBX1和HOXA10存在于基因表达之前的成骨细胞相关基因启动子上，但是在包括osterix（Osx）在内的骨相关基因转录过程中，启动子上没有PBX1。此外，PBX1复合物与通常与染色质失活有关的组蛋白脱乙酰基酶相关。 Osx启动子的PBX1而不是HOXA10的丢失与组蛋白乙酰化酶（p300）募集的增加以及H3K9甲基化的降低有关，反映了转录激活。我们建议PBX1在减弱HOXA10作为成骨细胞相关基因的激活剂的活动中起中心作用，并在成骨过程中建立适当的基因表达时机，从而在分化的成骨细胞中导致适当的基质成熟和矿物质沉积。

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