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RNA-seq analysis of Schwann cell knockout of ATP citrate lyase (ACLY)

ABSTRACT: Formation of myelin by Schwann cells is tightly coupled to nervous system development and is important for neuronal function and long-term maintenance. Perturbation of myelin causes a number of specific disorders that are among the most prevalent diseases affecting the nervous system. Schwann cells synthesize myelin lipids de novo rather than relying on uptake of circulating lipids, and the metabolic sources of myelin formation and maintenance in vivo remain unresolved. One of these questions is how a central metabolite in myelin formation, Acetyl CoA, is generated in myelinating cells. Acetyl CoA-generating pathways are induced at the level of gene expression to support high demands for lipid synthesis and acetylation reactions. However, recent studies have shown that glucose-derived Acetyl CoA itself is not required for myelination, and the requirements of mitochondrially-derived Acetyl CoA has never been tested for myelination in vivo. Several older labeling studies have demonstrated the possibility that cytosolic Acetyl CoA-generating pathways from acetate/ketone bodies satisfy the high demands for lipid synthesis and histone acetylation, and we have employed knockout mice to test the required pathways. Intriguingly, metabolic pathways play different role during the postnatal synthesis of myelin lipids in the postnatal period compared to myelin maintenance postweaning.

ORGANISM(S): Mus musculus

PROVIDER: GSE252209 | GEO | 2024/02/01

REPOSITORIES: GEO

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Project description:Cytosolic acetyl-coenzyme A is a precursor for many biotechnologically relevant compounds produced by Saccharomyces cerevisiae. In this yeast, cytosolic acetyl-CoA synthesis and growth strictly depend on expression of either the Acs1 or Acs2 isoenzyme of acetyl-CoA synthetase (ACS). Since hydrolysis of ATP to AMP and pyrophosphate in the ACS reaction constrains maximum yields of acetyl-CoA-derived products, this study explores replacement of ACS by two ATP-independent pathways for acetyl-CoA synthesis. After evaluating expression of different bacterial genes encoding acetylating acetaldehyde dehydrogenase (A-ALD) and pyruvate-formate lyase (PFL), acs1M-NM-^T acs2M-NM-^T S. cerevisiae strains were constructed in which A-ALD or PFL successfully replaced ACS. In A-ALD-dependent strains, aerobic growth rates of up to 0.27 h-1 were observed, while anaerobic growth rates of PFL-dependent S. cerevisiae (0.21 h-1) were stoichiometrically coupled to formate production. In glucose-limited chemostat cultures, intracellular metabolite analysis did not reveal major differences between A-ALD-dependent and reference strains. However, biomass yields on glucose of A-ALD- and PFL-dependent strains were lower than those of the reference strain. Transcriptome analysis suggested that reduced biomass yields were caused by acetaldehyde and formate in A-ALD- and PFL-dependent strains, respectively. Transcript profiles also indicated that a previously proposed role of Acs2 in histone acetylation is probably linked to cytosolic acetyl-CoA levels rather than to direct involvement of Acs2 in histone acetylation. While, for the first time, demonstrating that yeast ACS can be fully replaced by alternative reactions, this study demonstrates that further modifications are needed to achieve optimal in vivo efficiencies of the supply of acetyl-CoA as product precursor. To investigate the impact of introduced changes in native pathway of cytosolic acetyl-CoA formation in S. cerevisiae, a DNA microarray-based transcriptome analysis was performed on aerobic or anaerobic, glucose-limited chemostat cultures.

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RNA-seq analysis of Schwann cell knockout of ATP citrate lyase (ACLY)

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