State Key Laboratory of Oral Diseases, Department of Preventive Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041 Sichuan, China; West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, 610041 Sichuan, China; Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana 70118.
State Key Laboratory of Oral Diseases, Department of Preventive Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041 Sichuan, China; Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana 70118.
J Biol Chem. 2019 Nov 29;294(48):18294-18305. doi: 10.1074/jbc.RA119.008801. Epub 2019 Oct 24.
During mammalian palatogenesis, cranial neural crest-derived mesenchymal cells undergo osteogenic differentiation and form the hard palate, which is divided into palatine process of the maxilla and the palatine. However, it remains unknown whether these bony structures originate from the same cell lineage and how the hard palate is patterned at the molecular level. Using mice, here we report that deficiency in (), a transcriptional regulator whose expression is restricted to the anterior palatal mesenchyme, leads to a defective palatine process of the maxilla but does not affect the palatine. overexpression in palatal mesenchyme resulted in a hyperplastic palatine process of the maxilla and a hypoplastic palatine. RNA sequencing and assay for transposase-accessible chromatin-sequencing analyses revealed that Shox2 controls the expression of pattern specification and skeletogenic genes associated with accessible chromatin in the anterior palate. This highlighted a lineage-autonomous function of Shox2 in patterning and osteogenesis of the hard palate. H3K27ac ChIP-Seq and transient transgenic enhancer assays revealed that Shox2 binds distal-acting -regulatory elements in an anterior palate-specific manner. Our results suggest that the palatine process of the maxilla and palatine arise from different cell lineages and differ in ossification mechanisms. Shox2 evidently controls osteogenesis of a cell lineage and contributes to the palatine process of the maxilla by interacting with distal -regulatory elements to regulate skeletogenic gene expression and to pattern the hard palate. Genome-wide Shox2 occupancy in the developing palate may provide a marker for identifying active anterior palate-specific gene enhancers.
在哺乳动物腭发生过程中，颅神经嵴衍生的间充质细胞经历成骨分化并形成硬腭，硬腭分为上颌的腭突和腭。然而，尚不清楚这些骨结构是否源自同一细胞谱系，以及硬腭在分子水平上是如何模式化的。使用小鼠，我们在这里报告，转录调节因子（）的缺失，其表达仅限于腭中胚层的前区，导致上颌的腭突缺陷，但不影响腭。腭间充质中的过表达导致上颌的腭突过度增生和腭的发育不良。RNA 测序和转座酶可及染色质测序分析表明，Shox2 控制与前腭中胚层中可及染色质相关的模式特化和骨发生基因的表达。这突出了 Shox2 在硬腭模式化和骨发生中的谱系自主功能。H3K27ac ChIP-Seq 和瞬时转基因增强子分析表明，Shox2 以特定于前腭的方式结合远端作用的 -调控元件。我们的结果表明，上颌的腭突和腭来自不同的细胞谱系，其骨化机制不同。Shox2 显然通过与远端 -调控元件相互作用来控制细胞谱系的成骨作用，并通过调节骨发生基因的表达和硬腭的模式化来促进上颌的腭突。发育中的腭中的全基因组 Shox2 占据可能为鉴定活跃的前腭特异性基因增强子提供一个标记。
