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other·preclinical research, biomedical research, nutrition, neurology, pediatrics·PMC10304412

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

Nutrients · 5 authors, 2 centres

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TL;DR

This preclinical study used mouse models and in vitro neural progenitor cell assays to investigate how choline availability affects brain development. The central result was that low choline intake reduces SOX4 protein via upregulation of miR-129-5p, leading to decreased EZH2 and H3K27me3, which alters neural progenitor cell proliferation and differentiation.

Full summary

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The study investigated the molecular mechanism by which choline regulates neural development in a mouse model. Researchers demonstrated that low choline availability during neurogenesis reduces SOX4 protein levels in neural progenitor cells, not through protein degradation or synthesis changes, but via post-transcriptional regulation by microRNA miR-129-5p. Gain- and loss-of-function assays confirmed miR-129-5p targets SOX4. The reduction in SOX4 led to decreased EZH2 expression and lower global H3K27me3 histone methylation in the developing cortex. This epigenetic change was associated with reduced proliferation and precocious differentiation of neural progenitor cells. The study is preclinical, relying on animal and cell line models, and notes limitations including reliance on indirect evidence for the direct epigenetic regulation of miR-129-5p. Findings suggest a novel pathway linking nutrient availability to brain development via a transcription factor and epigenetic modifications.

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other

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preclinical research

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AI pipeline

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ORIGINAL PAPER

PMC10304412

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

Nutrients

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ABSTRACT

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.

CITATION EXPORT

Evan M. Paules, Jorge A. Silva-Gomez, Walter B. Friday et al.. Choline Regulates SOX4 through miR-129-5p and Modifies H3K27me3 in the Developing Cortex. Nutrients. (2023). https://doi.org/10.3390/nu15122774

AUTHORS

5 · 2 CENTRES

Evan M. Paules, Jorge A. Silva-Gomez, Walter B. Friday, Steve H. Zeisel, Isis Trujillo-Gonzalez

1Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA; [email protected] (E.M.P.); [email protected] (J.A.S.-G.); [email protected] (W.B.F.); [email protected] (S.H.Z.)
2Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC 28081, USA

EDITOR / REVIEWER

Edward Quadros