Saturated fatty acid alters embryonic cortical neurogenesis through modulation of gene expression in neural stem cells
Saturated fatty acid alters embryonic cortical neurogenesis through modulation of gene expression in neural stem cells
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DOI：
10.1016/j.jnutbio.2018.09.006
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发表时间：
2018-12-01
影响因子：
5.6
通讯作者：
Ansari, Suraiya A.
中科院分区：
文献类型：
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作者：
Ardah, Mustafa T.;Parween, Shama;Ansari, Suraiya A.
母体代谢环境的紊乱，如循环游离脂肪酸的长期升高，已被证明会影响胚胎神经发生期间干细胞的命运。然而，这背后的分子机制尚未明确，特别是在人类中。在这里，在使用人胚胎干细胞（hESC）定向分化为皮质神经元作为模型，我们表明，长期升高的饱和脂肪酸（棕榈酸）的结果在神经干细胞的增殖减少和增加分化为神经元。这种表型可能是由于棕榈酸酯介导的神经元分化所需的关键基因（如EOMES、TBRI、NEURODI和EPON）的表达增加以及皮质分化早期SREBP调节的脂肪生成基因的表达减少。此外，棕榈酸酯治疗增加组蛋白乙酰化全球和受影响的基因中的选择基因启动子。我们还发现了与细胞应激和代谢疾病相关的几种lncRNA的差异表达，在棕榈酸盐的存在下，包括BDNF-AS，这表明了额外的表观遗传调控机制的贡献。总之，我们的研究结果表明，饱和脂肪酸通过调节基因表达和表观遗传调控机制影响发育神经发生。(C)2018爱思唯尔公司All rights reserved.
A perturbed maternal metabolic environment such as chronically elevated circulating free fatty acids have been shown to affect stem cell fate during embryonic neurogenesis. However, molecular mechanisms behind this are not well defined, especially in human. Here in using directed differentiation of human embryonic stem cells (hESCs) into cortical neurons as model, we show that chronically elevated saturated fatty acid (palmitate) results in decreased proliferation of neural stem cells and increased differentiation into neurons. This phenotype could be due to palmitate mediated increased expression of key genes needed for neuronal differentiation such as EOMES, TBRI, NEURODI and RELN and reduced expression of SREBP regulated lipogenic genes at early stages of cortical differentiation. Furthermore, palmitate treatment increased histone acetylation globally and at select gene promoters among affected genes. We also found differential expression of several lncRNAs associated with cellular stress and metabolic diseases in the presence of palmitate including BDNF-AS suggesting the contribution of additional epigenetic regulatory mechanisms. Together, our results show that saturated fatty acid affects developmental neurogenesis through modulation of gene expression and through epigenetic regulatory mechanisms. (C) 2018 Elsevier Inc. All rights reserved.