Jacques-Fricke Bridget T, Gammill Laura S
Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN 55455.
Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN 55455
Mol Biol Cell. 2014 Dec 15;25(25):4174-86. doi: 10.1091/mbc.E13-12-0744. Epub 2014 Oct 15.
Neural crest precursors express genes that cause them to become migratory, multipotent cells, distinguishing them from adjacent stationary neural progenitors in the neurepithelium. Histone methylation spatiotemporally regulates neural crest gene expression; however, the protein methyltransferases active in neural crest precursors are unknown. Moreover, the regulation of methylation during the dynamic process of neural crest migration is unclear. Here we show that the lysine methyltransferase NSD3 is abundantly and specifically expressed in premigratory and migratory neural crest cells. NSD3 expression commences before up-regulation of neural crest genes, and NSD3 is necessary for expression of the neural plate border gene Msx1, as well as the key neural crest transcription factors Sox10, Snail2, Sox9, and FoxD3, but not gene expression generally. Nevertheless, only Sox10 histone H3 lysine 36 dimethylation requires NSD3, revealing unexpected complexity in NSD3-dependent neural crest gene regulation. In addition, by temporally limiting expression of a dominant negative to migratory stages, we identify a novel, direct requirement for NSD3-related methyltransferase activity in neural crest migration. These results identify NSD3 as the first protein methyltransferase essential for neural crest gene expression during specification and show that NSD3-related methyltransferase activity independently regulates migration.
神经嵴前体细胞表达的基因使它们成为可迁移的多能细胞，这将它们与神经上皮中相邻的静止神经祖细胞区分开来。组蛋白甲基化在时空上调节神经嵴基因的表达；然而，在神经嵴前体细胞中活跃的蛋白质甲基转移酶尚不清楚。此外，在神经嵴迁移的动态过程中甲基化的调节也不清楚。在这里，我们表明赖氨酸甲基转移酶NSD3在迁移前和迁移中的神经嵴细胞中大量且特异性地表达。NSD3的表达在神经嵴基因上调之前开始，并且NSD3对于神经板边界基因Msx1以及关键的神经嵴转录因子Sox10、Snail2、Sox9和FoxD3的表达是必需的，但并非对一般基因表达都必需。尽管如此，只有Sox10组蛋白H3赖氨酸36二甲基化需要NSD3，这揭示了NSD3依赖型神经嵴基因调控中意想不到的复杂性。此外，通过在迁移阶段暂时限制显性负性蛋白的表达，我们确定了神经嵴迁移中对NSD3相关甲基转移酶活性的一种新的直接需求。这些结果确定NSD3是在特化过程中神经嵴基因表达所必需的首个蛋白质甲基转移酶，并表明NSD3相关甲基转移酶活性独立调节迁移。
