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

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. Specifica...

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Autores principales: Paules, Evan M., Silva-Gomez, Jorge A., Friday, Walter B., Zeisel, Steve H., Trujillo-Gonzalez, Isis
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10304412/
https://www.ncbi.nlm.nih.gov/pubmed/37375678
http://dx.doi.org/10.3390/nu15122774
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author Paules, Evan M.
Silva-Gomez, Jorge A.
Friday, Walter B.
Zeisel, Steve H.
Trujillo-Gonzalez, Isis
author_facet Paules, Evan M.
Silva-Gomez, Jorge A.
Friday, Walter B.
Zeisel, Steve H.
Trujillo-Gonzalez, Isis
author_sort Paules, Evan M.
collection PubMed
description 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.
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spelling pubmed-103044122023-06-29 Choline Regulates SOX4 through miR-129-5p and Modifies H3K27me3 in the Developing Cortex Paules, Evan M. Silva-Gomez, Jorge A. Friday, Walter B. Zeisel, Steve H. Trujillo-Gonzalez, Isis Nutrients Article 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. MDPI 2023-06-16 /pmc/articles/PMC10304412/ /pubmed/37375678 http://dx.doi.org/10.3390/nu15122774 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Paules, Evan M.
Silva-Gomez, Jorge A.
Friday, Walter B.
Zeisel, Steve H.
Trujillo-Gonzalez, Isis
Choline Regulates SOX4 through miR-129-5p and Modifies H3K27me3 in the Developing Cortex
title Choline Regulates SOX4 through miR-129-5p and Modifies H3K27me3 in the Developing Cortex
title_full Choline Regulates SOX4 through miR-129-5p and Modifies H3K27me3 in the Developing Cortex
title_fullStr Choline Regulates SOX4 through miR-129-5p and Modifies H3K27me3 in the Developing Cortex
title_full_unstemmed Choline Regulates SOX4 through miR-129-5p and Modifies H3K27me3 in the Developing Cortex
title_short Choline Regulates SOX4 through miR-129-5p and Modifies H3K27me3 in the Developing Cortex
title_sort choline regulates sox4 through mir-129-5p and modifies h3k27me3 in the developing cortex
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10304412/
https://www.ncbi.nlm.nih.gov/pubmed/37375678
http://dx.doi.org/10.3390/nu15122774
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