Glucose oxidation and nutrients availability drive neural crest development

Nekooie-Marnany, Nioosha; Fodil, Rédouane; Féréol, Sophie; Depp, Marine; Motterlini, Roberto; Foresti, Roberta; Duband, Jean‐Loup; Dufour, Sylvie

doi:10.1101/2022.09.05.506657

Cited by 3 publications

(1 citation statement)

References 64 publications

(93 reference statements)

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“…In embryonic mouse development, the delaminating neural crest undergoes metabolic reprogramming towards aerobic glycolysis (Warburg effect) through a mechanism known to initiate expression of transcription factors to promote the epithelial-to-mesenchymal transition (EMT) 45 . More recent evidence in the avian neural crest supports that enhanced glycolysis, mitochondrial respiration, and the pentose phosphate pathway jointly mobilize to achieve coordination of EMT and migration 82 . At later stages, during melanocyte specification, the melanocyte (hair follicle) stem cell transcription factor Yin Yang 1 (YY1) couples MITF with metabolism gene expression and is essential for melanoma development 83, 84 .…”

Section: Discussionmentioning

confidence: 95%

ALDH1A3-acetaldehyde re-wires neural crest stem cell and high metabolism states to potentiate melanoma heterogeneity

Lu,

Travnickova,

Badonyi

et al. 2023

Preprint

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Cancer cellular heterogeneity and therapy resistance arise from metabolic and transcriptional adaptations, but how these are interconnected is less well understood. Here, we show that in melanoma, the cancer stem cell marker aldehyde dehydrogenase 1A3 (ALDH1A3) forms an enzymatic partnership with acetyl-CoA synthetase 2 (ACSS2) in the nucleus to couple high glucose metabolic flux with acetyl-histone H3 modification of neural crest lineage and glucose metabolism genes. Critically, we show acetaldehyde is a metabolite source for acetyl-histone H3 modification dependent on ALDH1A3, providing a physiologic function for this highly volatile and toxic metabolite. In a zebrafish model of melanoma residual disease, a subpopulation of ALDH1A3-high cells emerges following BRAF inhibitor treatment and targeting these with an ALDH1 suicide inhibitor, nifurtimox, delays or prevents BRAF inhibitor drug-resistant relapse. Our work reveals that ALDH1A3-ACSS2 directly coordinates local acetaldehyde-acetyl-CoA metabolism with specific chromatin-based gene regulation and represents a potential therapeutic vulnerability in melanoma.HighlightsALDH1A3-high melanomas are in a high glucose metabolic flux and neural crest stem cell dual state.Nuclear ALDH1A3 partners with ACSS2 to promote selective acetyl-histone H3.Acetaldehyde is an acetyl source for ALDH1A3 dependent histone H3 acetylation.ALDH1A3 is a master regulator and pharmaceutical target of melanoma heterogeneity.Graphical Abstract

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Section: Discussionmentioning

confidence: 95%

ALDH1A3-acetaldehyde re-wires neural crest stem cell and high metabolism states to potentiate melanoma heterogeneity

Lu,

Travnickova,

Badonyi

et al. 2023

Preprint

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Cholesterol biosynthesis modulates differentiation in murine cranial neural crest cells

Pascual

Icyuz

Karmaus

et al. 2023

Sci Rep

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Cranial neural crest cells (cNCC) are a multipotent embryonic cell population that give rise to a diverse set of cell types. These cells are particularly vulnerable to external metabolic stressors, as exemplified by the association between maternal hyperglycemia and congenital malformations. We were interested in studying the effect of various concentrations of glucose and pyruvate on cNCC metabolism, migration, and differentiation using an established murine neural crest cell model (O9-1). We unexpectedly observed a pattern of gene expression suggestive of cholesterol biosynthesis induction under glucose depletion conditions in O9-1 cells. We further showed that treatment with two different cholesterol synthesis inhibitors interfered with cell migration and differentiation, inhibiting chondrogenesis while enhancing smooth muscle cell differentiation. As congenital arhinia (absent external nose), a malformation caused by mutations in SMCHD1, appears to represent, in part, a defect in cNCC, we were also interested in investigating the effects of glucose and cholesterol availability on Smchd1 expression in O9-1 cells. Smchd1 expression was induced under high glucose conditions whereas cholesterol synthesis inhibitors decreased Smchd1 expression during chondrogenesis. These data highlight a novel role for cholesterol biosynthesis in cNCC physiology and demonstrate that human phenotypic variability in SMCHD1 mutation carriers may be related, in part, to SMCHD1’s sensitivity to glucose or cholesterol dosage during development.

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Sphingolipid metabolism is spatially regulated in the developing embryo bySOXEgenes

Piacentino,

Fasse,

Camacho-Avila

et al. 2023

Preprint

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During epithelial-to-mesenchymal transition (EMT), significant rearrangements occur in plasma membrane protein and lipid content that are important for membrane function and acquisition of cell motility. To gain insight into how neural crest cells regulate their lipid content at the transcriptional level during EMT, here we identify critical enhancer sequences that regulate the expression of SMPD3, a gene responsible for sphingomyelin hydrolysis to produce ceramide, which is necessary for neural crest EMT. We uncovered three enhancer regions within the first intron of the SMPD3 locus that drive reporter expression in distinct spatial and temporal domains, together collectively recapitulating the expression domains of endogenous SMPD3 within the ectodermal lineages. We further dissected one enhancer that is specifically active in the migrating neural crest. By mutating putative transcriptional input sites or knocking down upstream regulators, we find that the SoxE-family transcription factors Sox9 and Sox10 regulate the expression of SMPD3 in migrating neural crest cells. Together these results shed light on how core components of developmental gene regulatory networks interact with metabolic effector genes to control changes in membrane lipid content.

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Glucose oxidation and nutrients availability drive neural crest development

Cited by 3 publications

References 64 publications

ALDH1A3-acetaldehyde re-wires neural crest stem cell and high metabolism states to potentiate melanoma heterogeneity

ALDH1A3-acetaldehyde re-wires neural crest stem cell and high metabolism states to potentiate melanoma heterogeneity

Cholesterol biosynthesis modulates differentiation in murine cranial neural crest cells

Sphingolipid metabolism is spatially regulated in the developing embryo bySOXEgenes

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