Choline Regulates SOX4 through miR-129-5p and Modifies H3K27me3 in the Developing Cortex

被引:2
作者
Paules, Evan M. [1 ]
Silva-Gomez, Jorge A. [1 ]
Friday, Walter B. [1 ]
Zeisel, Steve H. [1 ,2 ]
Trujillo-Gonzalez, Isis [1 ,2 ]
机构
[1] Univ North Carolina Chapel Hill, Gillings Sch Global Publ Hlth, Dept Nutr, Chapel Hill, NC 27514 USA
[2] Univ North Carolina Chapel Hill, Nutr Res Inst, Kannapolis, NC 28081 USA
基金
美国国家卫生研究院;
关键词
choline; SOX4; EZH2; miR-125-9p; maternal nutrition; EPITHELIAL-MESENCHYMAL TRANSITION; DNA METHYLATION; DIETARY CHOLINE; BRAIN-DEVELOPMENT; MATERNAL CHOLINE; DIFFERENTIATION; EXPRESSION; ALTERS; CELLS; EZH2;
D O I
10.3390/nu15122774
中图分类号
R15 [营养卫生、食品卫生]; TS201 [基础科学];
学科分类号
100403 ;
摘要
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.
引用
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页数:19
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