HMGN2 represses gene transcription via interaction with transcription factors Lef-1 and Pitx2 during amelogenesis.
HMGN2 represses gene transcription via interaction with transcription factors Lef-1 and Pitx2 during amelogenesis.
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DOI：
10.1016/j.jbc.2022.102295
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发表时间：
2022-09
影响因子：
4.8
通讯作者：
Amendt, Brad A.
中科院分区：
文献类型：
--
作者：
Eliason, Steven;Su, Dan;Pinho, Flavia;Sun, Zhao;Zhang, Zichao;Li, Xiao;Sweat, Mason;Venugopalan, Shankar R.;He, Bing;Bustin, Michael;Amendt, Brad A.
染色质相关高迁移率族蛋白N2（HMGN 2）辅因子通过染色质和蛋白质相互作用调节转录因子活性。已知Hmgn 2表达受发育调控，但调控Hmgn 2表达的转录后机制及其在牙齿发育中的确切作用仍不清楚。在这里，我们证明了HMGN 2抑制多种转录因子的活性作为一种一般机制来调节早期发育。双分子荧光互补，下拉和免疫共沉淀试验表明，HMGN 2通过其HMG盒结构域与转录因子Lef-1相互作用，以及与其他早期发育转录因子Dlx 2，FoxJ 1和Pitx 2相互作用。此外，EMSA证明HMGN 2与Lef-1的结合抑制其DNA结合活性。我们发现Pitx 2和Hmgn 2与近端Dlx 2启动子中的H4 K5 ac和H3 K4 me 2染色质标记相关，表明Hmgn 2与开放染色质相关。此外，我们证明了microRNAs（miRs）mir-23 a和miR-23 b直接靶向Hmgn 2，促进几个基因启动子（包括釉原蛋白启动子）的转录激活。在体内，我们发现随着小鼠胚胎的发育，颅面组织中Hmgn 2表达的降低与miR-23表达的增加相关。最后，我们表明，在小鼠中的Hmgn 2的消融增加釉原蛋白的表达，因为增加的Pitx 2，Dlx 2，Lef-1和FoxJ 1的转录活性。综上所述，我们的研究结果表明，Hmgn 2的转录后调控的miR-23 a/B和翻译后调控的基因表达的Hmgn 2-转录因子的相互作用。我们的结论是，HMGN 2调控牙齿发育，通过其与多种转录因子的相互作用。
The chromatin-associated high mobility group protein N2 (HMGN2) cofactor regulates transcription factor activity through both chromatin and protein interactions. Hmgn2 expression is known to be developmentally regulated, but the post-transcriptional mechanisms that regulate Hmgn2 expression and its precise roles in tooth development remain unclear. Here, we demonstrate that HMGN2 inhibits the activity of multiple transcription factors as a general mechanism to regulate early development. Bimolecular fluorescence complementation, pull-down, and coimmunoprecipitation assays show that HMGN2 interacts with the transcription factor Lef-1 through its HMG-box domain as well as with other early development transcription factors, Dlx2, FoxJ1, and Pitx2. Furthermore, EMSAs demonstrate that HMGN2 binding to Lef-1 inhibits its DNA-binding activity. We found that Pitx2 and Hmgn2 associate with H4K5ac and H3K4me2 chromatin marks in the proximal Dlx2 promoter, demonstrating Hmgn2 association with open chromatin. In addition, we demonstrate that microRNAs (miRs) mir-23a and miR-23b directly target Hmgn2, promoting transcriptional activation at several gene promoters, including the amelogenin promoter. In vivo, we found that decreased Hmgn2 expression correlates with increased miR-23 expression in craniofacial tissues as the murine embryo develops. Finally, we show that ablation of Hmgn2 in mice results in increased amelogenin expression because of increased Pitx2, Dlx2, Lef-1, and FoxJ1 transcriptional activity. Taken together, our results demonstrate both post-transcriptional regulation of Hmgn2 by miR-23a/b and post-translational regulation of gene expression by Hmgn2–transcription factor interactions. We conclude that HMGN2 regulates tooth development through its interaction with multiple transcription factors.
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