Cholesterol synthesis-related enzyme oxidosqualene cyclase is required to maintain self-renewal in primary erythroid progenitors

Mejia-Pous, Camila; Damiola, Francesca; Gandrillon, Olivier

doi:10.1111/j.1365-2184.2011.00771.x

Cited by 16 publications

(21 citation statements)

References 54 publications

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“…Gene ontology analysis using the DAVID database [60] revealed a clear over-representation of genes involved in sterol biosynthesis in this list (not shown). This finding was in line with our previous analysis showing that the oxydosqualene cyclase (OSC), which is involved in cholesterol synthesis, is required to maintain self-renewal in T2EC [35]. However, no other over-represented function emerged from the present analysis.…”

Section: Resultssupporting

confidence: 93%

“…We therefore can propose that the sterol synthesis pathway could act as one of the drivers of the changes that will update the internal network from the changes in external conditions. This would be in line with our previous demonstration for the role of cholesterol synthesis in the decision making process in our cells [35]. …”

Section: Resultssupporting

confidence: 93%

“…The question as to why this group of genes act as the early sensors of change in environmental conditions remains elusive. In line with our previous results [35], one could hypothesize that cholesterol synthesis is a barrier toward differentiation/apoptosis that has to be lowered for differentiation to proceed.…”

Section: Discussionsupporting

confidence: 91%

“…The primary cause for differentiation is therefore known and relies upon change in the information carried by the extracellular environment. The differentiation process in those cells has been previously analyzed at the population level [33–35]. …”

Section: Introductionmentioning

confidence: 99%

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Single-Cell-Based Analysis Highlights a Surge in Cell-to-Cell Molecular Variability Preceding Irreversible Commitment in a Differentiation Process

et al. 2016

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In some recent studies, a view emerged that stochastic dynamics governing the switching of cells from one differentiation state to another could be characterized by a peak in gene expression variability at the point of fate commitment. We have tested this hypothesis at the single-cell level by analyzing primary chicken erythroid progenitors through their differentiation process and measuring the expression of selected genes at six sequential time-points after induction of differentiation. In contrast to population-based expression data, single-cell gene expression data revealed a high cell-to-cell variability, which was masked by averaging. We were able to show that the correlation network was a very dynamical entity and that a subgroup of genes tend to follow the predictions from the dynamical network biomarker (DNB) theory. In addition, we also identified a small group of functionally related genes encoding proteins involved in sterol synthesis that could act as the initial drivers of the differentiation. In order to assess quantitatively the cell-to-cell variability in gene expression and its evolution in time, we used Shannon entropy as a measure of the heterogeneity. Entropy values showed a significant increase in the first 8 h of the differentiation process, reaching a peak between 8 and 24 h, before decreasing to significantly lower values. Moreover, we observed that the previous point of maximum entropy precedes two paramount key points: an irreversible commitment to differentiation between 24 and 48 h followed by a significant increase in cell size variability at 48 h. In conclusion, when analyzed at the single cell level, the differentiation process looks very different from its classical population average view. New observables (like entropy) can be computed, the behavior of which is fully compatible with the idea that differentiation is not a “simple” program that all cells execute identically but results from the dynamical behavior of the underlying molecular network.

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Section: Resultssupporting

confidence: 93%

Section: Resultssupporting

confidence: 93%

Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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Single-Cell-Based Analysis Highlights a Surge in Cell-to-Cell Molecular Variability Preceding Irreversible Commitment in a Differentiation Process

et al. 2016

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“…36 We therefore assessed different parameters of the glycolytic metabolism during the 37 first three days of primary avian erythroid progenitor cells differentiation. We first 38 analyzed the protein level of a few key enzymes involved either in glycolysis or 39 OXPHOS pathway, at six time-points of the differentiation process. To confirm our 40 results at the physiological level we then compared lactate production, indicating 41 glycolytic rate, and mitochondrial membrane potential (MMP), that partially reflects 42 OXPHOS activity, of self-renewing and differentiating cells.…”

mentioning

confidence: 99%

Erythroid differentiation displays a peak of energy consumption concomitant with glycolytic metabolism rearrangements

Angélique

Vallin

Romestaing

et al. 2019

Preprint

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Author summarySingle-cell based gene expression data from one of our previous publication pointed out significant variations of LDHA level, an important metabolism player, during erythroid differentiation. Deeper investigations highlighted that a metabolic switch occurred along differentiation of erythroid cells as previously emphasized in stem cell differentiation. More precisely our finding showed that self-renewing progenitor cells relied mostly upon a glycolytic, lactate-productive, metabolism and required LDHA activity, whereas differentiating cells, mainly involved the aerobic mitochondrial oxidative phosphorylation (OXPHOS). However our careful kinetic study demonstrated that these metabolic rearrangements were coming along with a particular temporary event, occurring within the first 24h of erythroid differentiation. The activity of glycolytic metabolism and OXPHOS rose jointly with ATP production at 12-24h of the differentiation process before lactate-productive glycolysis sharply fall down and energy needs decline. Finally, our results showed that the metabolic switch mediated through LDHA drop and OXPHOS upkeep might be necessary for erythroid differentiation. We also discuss the possibility that metabolism, gene expression and epigenetics could act together in a circular manner as a driving force for differentiation. Introduction 1Metabolism is a biological process mostly involved in energy consumption, production 2 and distribution, which is essential for cell functions and survival.3 An emerging theme is the possible causal involvement of metabolic changes during a 4 differentiation process. In particular, glycolysis was shown to be characteristic of 5 self-renewing stem cells and of different types of progenitors, such as neuronal and 6 hematopoietic progenitor cells [1,2]. It has been demonstrated that stem cells tend to 7 switch from glycolytic metabolism toward mitochondrial oxidative phosphorylation 8 (OXPHOS) while they differentiate [3][4][5]. Accordingly, it was suggested that a balance 9 between glycolysis and OXPHOS metabolism could somehow guide the choice between 10 self-renewal and differentiation in stem cells fate [6]. It has also been demonstrated that 11 preventing the shutting down of the glycolytic pathway was detrimental for neuronal 12 differentiation [4]. Otherwise, regarding somatic cells reprogramming into induced 13 pluripotent stem cells, it has been reported that pluripotency induction required the 14 concomitant upregulation of glycolytic metabolism and downregulation of OXPHOS [7]. 15 Regarding erythroid differentiation, progenitors depend on glycolysis and present a 16 Warburg-like profile as they display a high proliferation rate and produce an abundant 17 amount of lactate [8]. However, few is known about glucose metabolism behavior during 18 erythroid differentiation, when compared to erythroid progenitors self-renewal. Mature 19 mammals erythrocytes were shown to rely upon lactate dehydrogenase to fulfill their 20 functions, depending therefore upon the glycolytic p...

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2,3-Oxidosqualene cyclase protects liver cells from the injury of intermittent hypoxia by regulating lipid metabolism

Zhen

Yanhong

et al. 2015

Sleep Breath

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Purpose2,3-Oxidosqualene cyclase (OSC), an important enzyme of cholesterol biosynthesis, catalyzes the highly selective cyclization of 2,3-monoepoxysqualene to lanosterol. Intermittent hypoxia (IH) is a hallmark feature in obstructive sleep apnea (OSA) which is increasingly recognized as an independent risk factor for liver injury. The aim of this study was to determine the effect of IH on OSC expression and evaluate the role of OSC in the IH-induced apoptosis in hepatic cell line human liver cell (HL-02).MethodsHL-02 cells were exposed to normoxia or IH. Cell Counting Kit-8 (CCK-8) assay was used to value cell proliferation, and flow cytometry was used to determine cell apoptosis. The expression of OSC messenger RNA (mRNA) was evaluated by quantitative real-time PCR, and the expression of OSC protein was determined by Western blot. To further investigate the function of OSC in IH-induced apoptosis, oxidosqualene cyclase-enhanced green fluorescence protein (OSC-EGFP) plasmid was constructed to over-express OSC protein. Triglyceride content in HL-02 cells was analyzed by oil red staining or Triglyceride Quantification Kit.ResultsWe found that IH inhibited HL-02 cell proliferation and accelerated cell apoptosis. IH decreased OSC expression, and over-expression of OSC could protect HL-02 cells against the IH-induced hepatic cell injury. Moreover, over-expression of OSC could attenuate IH-induced cellular triglyceride accumulation.ConclusionsThese findings suggest that OSC are involved in IH-induced hepatic cell injury. These results may contribute to the further understanding of the mechanism underlying the liver injury in OSA patients.

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Cholesterol synthesis-related enzyme oxidosqualene cyclase is required to maintain self-renewal in primary erythroid progenitors

Abstract: Taken together, our results suggest that OSC/LSS expression and activity are required to maintain cell self-renewal and may be involved in the self-renewal versus differentiation/apoptosis decision making, by keeping cells in a self-renewal state.

Cited by 16 publications

References 54 publications

Single-Cell-Based Analysis Highlights a Surge in Cell-to-Cell Molecular Variability Preceding Irreversible Commitment in a Differentiation Process

Single-Cell-Based Analysis Highlights a Surge in Cell-to-Cell Molecular Variability Preceding Irreversible Commitment in a Differentiation Process

Erythroid differentiation displays a peak of energy consumption concomitant with glycolytic metabolism rearrangements

2,3-Oxidosqualene cyclase protects liver cells from the injury of intermittent hypoxia by regulating lipid metabolism

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