State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, Hubei 430079, China.
State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, Hubei 430079, China; Department of Cariology and Endodontics, School of Stomatology, Wuhan University, Wuhan, Hubei 430079, China.
J Genet Genomics. 2023 Jul;50(7):497-510. doi: 10.1016/j.jgg.2023.02.005. Epub 2023 Feb 19.
Mouse dental papilla cells (mDPCs) are cranial neural crest-derived dental mesenchymal cells that give rise to dentin-secreting odontoblasts after the bell stage during odontogenesis. The odontoblastic differentiation of mDPCs is spatiotemporally regulated by transcription factors (TFs). Our previous work reveals that chromatin accessibility was correlated with the occupation of the basic leucine zipper TF family during odontoblastic differentiation. However, the detailed mechanism by which TFs regulate the initiation of odontoblastic differentiation remains elusive. Here, we report that phosphorylation of ATF2 (p-ATF2) is particularly increased during odontoblastic differentiation in vivo and in vitro. ATAC-seq and p-ATF2 CUT&Tag experiments further demonstrate a high correlation between p-ATF2 localization and increased chromatin accessibility of regions near mineralization-related genes. Knockdown of Atf2 inhibits the odontoblastic differentiation of mDPCs, while overexpression of p-ATF2 promotes odontoblastic differentiation. ATAC-seq after overexpression of p-ATF2 reveals that p-ATF2 increases the chromatin accessibility of regions adjacent to genes associated with matrix mineralization. Furthermore, we find that p-ATF2 physically interacts with and promotes H2BK12 acetylation. Taken together, our findings reveal a mechanism that p-ATF2 promotes odontoblastic differentiation at initiation via remodeling chromatin accessibility and emphasize the role of the phosphoswitch model of TFs in cell fate transitions.
小鼠牙乳头细胞（mDPC）是颅神经嵴衍生的牙间充质细胞，在牙发生的钟状期后分化为分泌牙本质的成牙本质细胞。mDPC 的成牙本质细胞分化是受转录因子（TFs）时空调节的。我们之前的工作表明，染色质可及性与成牙本质分化过程中碱性亮氨酸拉链 TF 家族的占据有关。然而，TFs 调节成牙本质细胞分化起始的详细机制仍不清楚。在这里，我们报告在体内和体外成牙本质分化过程中 p-ATF2 的磷酸化（p-ATF2）特别增加。ATAC-seq 和 p-ATF2 CUT&Tag 实验进一步证明了 p-ATF2 定位与矿化相关基因附近区域染色质可及性增加之间的高度相关性。Atf2 的敲低抑制 mDPC 的成牙本质细胞分化，而过表达 p-ATF2 则促进成牙本质细胞分化。过表达 p-ATF2 后的 ATAC-seq 显示，p-ATF2 增加了与基质矿化相关基因相邻区域的染色质可及性。此外，我们发现 p-ATF2 与 H2BK12 乙酰化相互作用并促进其发生。总之，我们的研究结果揭示了 p-ATF2 通过重塑染色质可及性促进起始阶段成牙本质细胞分化的机制，并强调了 TF 的磷酸开关模型在细胞命运转变中的作用。
