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Folate Carrier Deficiency Drives Differential Methylation and Enhanced Cellular Potency in the Neural Plate Border

The neural plate border (NPB) of vertebrate embryos segregates from the neural and epidermal regions, and it is comprised of an intermingled group of multipotent progenitor cells. Folate is the precursor of S-adenosylmethionine, the main methyl donor for DNA methylation, and it is critical for embry...

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Autores principales: Alata Jimenez, Nagif, Strobl-Mazzulla, Pablo H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9326018/
https://www.ncbi.nlm.nih.gov/pubmed/35912103
http://dx.doi.org/10.3389/fcell.2022.834625
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author Alata Jimenez, Nagif
Strobl-Mazzulla, Pablo H.
author_facet Alata Jimenez, Nagif
Strobl-Mazzulla, Pablo H.
author_sort Alata Jimenez, Nagif
collection PubMed
description The neural plate border (NPB) of vertebrate embryos segregates from the neural and epidermal regions, and it is comprised of an intermingled group of multipotent progenitor cells. Folate is the precursor of S-adenosylmethionine, the main methyl donor for DNA methylation, and it is critical for embryonic development, including the specification of progenitors which reside in the NPB. Despite the fact that several intersecting signals involved in the specification and territorial restriction of NPB cells are known, the role of epigenetics, particularly DNA methylation, has been a matter of debate. Here, we examined the temporal and spatial distribution of the methyl source and analyzed the abundance of 5mC/5 hmC and their epigenetic writers throughout the segregation of the neural and NPB territories. Reduced representation bisulfite sequencing (RRBS) on Reduced Folate Carrier 1 (RFC1)-deficient embryos leads to the identification of differentially methylated regions (DMRs). In the RFC1-deficient embryos, we identified several DMRs in the Notch1 locus, and the spatiotemporal expression of Notch1 and its downstream target gene Bmp4 were expanded in the NPB. Cell fate analysis on folate deficient embryos revealed a significant increase in the number of cells coexpressing both neural (SOX2) and NPB (PAX7) markers, which may represent an enhancing effect in the cellular potential of those progenitors. Taken together, our findings propose a model where the RFC1 deficiency drives methylation changes in specific genomic regions that are correlated with a dysregulation of pathways involved in early development such as Notch1 and BMP4 signaling. These changes affect the potency of the progenitors residing in the juncture of the neural plate and NPB territories, thus driving them to a primed state.
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spelling pubmed-93260182022-07-28 Folate Carrier Deficiency Drives Differential Methylation and Enhanced Cellular Potency in the Neural Plate Border Alata Jimenez, Nagif Strobl-Mazzulla, Pablo H. Front Cell Dev Biol Cell and Developmental Biology The neural plate border (NPB) of vertebrate embryos segregates from the neural and epidermal regions, and it is comprised of an intermingled group of multipotent progenitor cells. Folate is the precursor of S-adenosylmethionine, the main methyl donor for DNA methylation, and it is critical for embryonic development, including the specification of progenitors which reside in the NPB. Despite the fact that several intersecting signals involved in the specification and territorial restriction of NPB cells are known, the role of epigenetics, particularly DNA methylation, has been a matter of debate. Here, we examined the temporal and spatial distribution of the methyl source and analyzed the abundance of 5mC/5 hmC and their epigenetic writers throughout the segregation of the neural and NPB territories. Reduced representation bisulfite sequencing (RRBS) on Reduced Folate Carrier 1 (RFC1)-deficient embryos leads to the identification of differentially methylated regions (DMRs). In the RFC1-deficient embryos, we identified several DMRs in the Notch1 locus, and the spatiotemporal expression of Notch1 and its downstream target gene Bmp4 were expanded in the NPB. Cell fate analysis on folate deficient embryos revealed a significant increase in the number of cells coexpressing both neural (SOX2) and NPB (PAX7) markers, which may represent an enhancing effect in the cellular potential of those progenitors. Taken together, our findings propose a model where the RFC1 deficiency drives methylation changes in specific genomic regions that are correlated with a dysregulation of pathways involved in early development such as Notch1 and BMP4 signaling. These changes affect the potency of the progenitors residing in the juncture of the neural plate and NPB territories, thus driving them to a primed state. Frontiers Media S.A. 2022-07-13 /pmc/articles/PMC9326018/ /pubmed/35912103 http://dx.doi.org/10.3389/fcell.2022.834625 Text en Copyright © 2022 Alata Jimenez and Strobl-Mazzulla. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Alata Jimenez, Nagif
Strobl-Mazzulla, Pablo H.
Folate Carrier Deficiency Drives Differential Methylation and Enhanced Cellular Potency in the Neural Plate Border
title Folate Carrier Deficiency Drives Differential Methylation and Enhanced Cellular Potency in the Neural Plate Border
title_full Folate Carrier Deficiency Drives Differential Methylation and Enhanced Cellular Potency in the Neural Plate Border
title_fullStr Folate Carrier Deficiency Drives Differential Methylation and Enhanced Cellular Potency in the Neural Plate Border
title_full_unstemmed Folate Carrier Deficiency Drives Differential Methylation and Enhanced Cellular Potency in the Neural Plate Border
title_short Folate Carrier Deficiency Drives Differential Methylation and Enhanced Cellular Potency in the Neural Plate Border
title_sort folate carrier deficiency drives differential methylation and enhanced cellular potency in the neural plate border
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9326018/
https://www.ncbi.nlm.nih.gov/pubmed/35912103
http://dx.doi.org/10.3389/fcell.2022.834625
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