Changes in Hox Gene Chromatin Organization during Odontogenic Lineage Specification.
Changes in Hox Gene Chromatin Organization during Odontogenic Lineage Specification.
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颅面组织包括高度进化的器官，其特征在于HOX家族转录因子的表达相对缺乏。在本研究中，我们试图定义的表观遗传事件，限制HOX基因表达从未分化的神经嵴细胞半分化的牙源性祖细胞，并探讨HOX水平升高的影响。ChIP芯片数据显示，与H3 K4 me 3标记相比，ES和颅神经嵴细胞中HOX基因启动子上的H3 K27 me 3标记具有高水平的抑制性，而K4/K27比率在牙源性祖细胞、牙囊、牙髓、牙周膜成纤维细胞、牙槽骨成骨细胞和成牙骨质细胞中的抑制性较低。多个HOX基因的基因表达，特别是HOXA和HOXB簇的基因表达，在牙槽骨细胞中显著升高，并且比牙囊细胞高出许多倍。此外，HOX在骨骼成骨细胞中的水平在躯干成骨细胞中比在牙槽骨成骨细胞中高许多倍，并且当与躯干成骨细胞相比时，在牙槽骨成骨细胞中抑制性标记H3 K27 me 3启动子占据率实质上显著升高。为了探索颅面神经嵴细胞中HOX水平升高的影响，通过用Cdx 4转录因子转染细胞来诱导HOX表达，导致HOX升高后矿化标记物RUNX 2、OSX和OCN显著降低。与对照组相比，使用小分子EZH 2抑制剂GSK 126促进HOX基因在发育中的牙齿中的表达导致图案化事件的数量增加，额外牙尖形成，以及Hoxa 4和Hoxb 6基因表达增加。总之，这些研究表明，在颅面外周组织从神经嵴分化的所有阶段，包括谱系规范，组织分化和图案化的表观遗传调控事件的深远影响。
Craniofacial tissues comprise highly evolved organs characterized by a relative lack of expression in the HOX family transcription factors. In the present study, we sought to define the epigenetic events that limit HOX gene expression from undifferentiated neural crest cells to semi-differentiated odontogenic progenitors and to explore the effects of elevated levels of HOX. The ChIP-chip data demonstrated high levels of repressive H3K27me3 marks on the HOX gene promoters in ES and cranial neural crest cells when compared to the H3K4me3 marks, while the K4/K27 ratio was less repressive in the odontogenic progenitors, dental follicle, dental pulp, periodontal ligament fibroblasts, alveolar bone osteoblasts, and cementoblasts. The gene expression of multiple HOX genes, especially those from the HOXA and HOXB clusters, was significantly elevated and many times higher in alveolar bone cells than in the dental follicle cells. In addition, the HOX levels in the skeletal osteoblasts were many times higher in the trunk osteoblasts compared to the alveolar bone osteoblasts, and the repressive mark H3K27me3 promoter occupancy was substantially and significantly elevated in the alveolar bone osteoblasts when compared to the trunk osteoblasts. To explore the effect of elevated HOX levels in craniofacial neural crest cells, HOX expression was induced by transfecting cells with the Cdx4 transcription factor, resulting in a significant decrease in the mineralization markers, RUNX2, OSX, and OCN upon HOX elevation. Promoting HOX gene expression in developing teeth using the small molecule EZH2 inhibitor GSK126 resulted in an increased number of patterning events, supernumerary cusp formation, and increased Hoxa4 and Hoxb6 gene expression when compared to the controls. Together, these studies illustrate the profound effects of epigenetic regulatory events at all stages of the differentiation of craniofacial peripheral tissues from the neural crest, including lineage specification, tissue differentiation, and patterning.
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