Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC 28081, USA.
Nutrients. 2023 Jun 16;15(12):2774. doi: 10.3390/nu15122774.
Choline availability regulates neural progenitor cell proliferation and differentiation in the developing cerebral cortex. Here, we investigated the molecular mechanism underlying this process and demonstrated that choline regulates the transcription factor SOX4 in neural progenitor cells. Specifically, we found that low choline intake during neurogenesis reduces SOX4 protein levels, causing the downregulation of EZH2, a histone methyltransferase. Importantly, we demonstrate that low choline is not involved in SOX4 protein degradation rate and established that protein reduction is caused by aberrant expression of a microRNA (miR-129-5p). To confirm the role of miR-129-5p, we conducted gain-of-function and loss-of-function assays in neural progenitor cells and demonstrated that directly altering miR-129-5p levels could affect SOX4 protein levels. We also observed that the reduction in SOX4 and EZH2 led to decreased global levels of H3K27me3 in the developing cortex, contributing to reduced proliferation and precocious differentiation. For the first time, to our knowledge, we demonstrate that a nutrient, choline, regulates a master transcription factor and its downstream targets, providing a novel insight into the role of choline in brain development.
胆碱供应调节发育中大脑皮层神经祖细胞的增殖和分化。在这里，我们研究了这一过程的分子机制，并证明胆碱在神经祖细胞中调节转录因子 SOX4。具体来说，我们发现神经发生过程中胆碱摄入不足会降低 SOX4 蛋白水平，导致组蛋白甲基转移酶 EZH2 的下调。重要的是，我们证明低胆碱并不参与 SOX4 蛋白降解率，并且确定蛋白减少是由 microRNA (miR-129-5p) 的异常表达引起的。为了证实 miR-129-5p 的作用，我们在神经祖细胞中进行了功能获得和功能丧失实验，结果表明直接改变 miR-129-5p 的水平可以影响 SOX4 蛋白水平。我们还观察到 SOX4 和 EZH2 的减少导致发育中皮层中 H3K27me3 的整体水平降低，从而导致增殖减少和早熟分化。据我们所知，这是首次证明一种营养素，胆碱，调节主转录因子及其下游靶标，为胆碱在大脑发育中的作用提供了新的见解。
