UNC Nutrition Research Institute at Kannapolis, University of North Carolina, 500 Laureate Way, Kannapolis, NC 28081, USA.
FASEB J. 2010 Jan;24(1):184-95. doi: 10.1096/fj.09-140145. Epub 2009 Sep 14.
Maternal choline availability is essential for fetal neurogenesis. Choline deprivation (CD) causes hypomethylation of specific CpG islands in genes controlling cell cycling in fetal hippocampus. We now report that, in C57BL/6 mice, CD during gestational days 12-17 also altered methylation of the histone H3 in E17 fetal hippocampi. In the ventricular and subventricular zones, monomethyl-lysine 9 of H3 (H3K9me1) was decreased by 25% (P<0.01), and in the pyramidal layer, dimethyl-lysine 9 of H3 (H3K9me2) was decreased by 37% (P<0.05). These changes were region specific and were not observed in whole-brain preparations. Also, the same effects of CD on H3 methylation were observed in E14 neural progenitor cells (NPCs) in culture. Changes in G9a histone methyltransferase might mediate altered H3K9me2,1. Gene expression of G9a was decreased by 80% in CD NPCs (P<0.001). In CD, H3 was hypomethylated upstream of the RE1 binding site in the calbindin 1 promoter, and 1 CpG site within the calbindin1 promoter was hypermethylated. REST binding to RE1 (recruits G9a) was decreased by 45% (P<0.01) in CD. These changes resulted in increased expression of calbindin 1 in CD (260%; P<0.05). Thus, CD modulates histone methylation in NPCs, and this could underlie the observed changes in neurogenesis.
母体胆碱供应对于胎儿神经发生至关重要。胆碱剥夺（CD）导致控制胎儿海马细胞周期的基因中特定 CpG 岛的低甲基化。我们现在报告，在 C57BL/6 小鼠中，妊娠第 12-17 天的 CD 也改变了 E17 胎儿海马中的组蛋白 H3 的甲基化。在脑室和脑室下区，H3 的单甲基赖氨酸 9（H3K9me1）减少了 25%（P<0.01），而在锥体层，H3 的二甲基赖氨酸 9（H3K9me2）减少了 37%（P<0.05）。这些变化具有区域特异性，在全脑制剂中未观察到。此外，在培养中的 E14 神经祖细胞（NPC）中也观察到 CD 对 H3 甲基化的相同影响。G9a 组蛋白甲基转移酶的变化可能介导了 H3K9me2,1 的改变。CD NPC 中的 G9a 基因表达减少了 80%（P<0.001）。在 CD 中，钙结合蛋白 1 启动子的 RE1 结合位点上游的 H3 被低甲基化，并且钙结合蛋白 1 启动子内的 1 个 CpG 位点被高甲基化。RE1 结合的 REST（招募 G9a）减少了 45%（P<0.01）。这些变化导致 CD 中钙结合蛋白 1 的表达增加了 260%（P<0.05）。因此，CD 调节 NPC 中的组蛋白甲基化，这可能是观察到的神经发生变化的基础。
