Dataset Information

Transcriptome-wide analysis of Agc1 downregulation in mouse oligodendrocyte precursor cells

ABSTRACT: Aspartate-glutamate carrier isoform 1 (Agc1) is a mitochondrial carrier part of the malate-aspartate shuttle, responsible for the export of aspartate and N-acetyl-aspartate from the mitochondria to the brain. Agc1 deficiency can cause an ultra-rare genetic disease reported as epileptic encephalopathy with global cerebral demyelination often caused by mutation in Slc25a12, the gene from which Agc1 is encoded. Symptoms of the disease include diffused hypomyelination, arrested psychomotor development, severe hypotonia, seizures and are common to other neurological and developmental disorders. Oligodendrocytes are glial cells responsible for myelination and remyelination and a disruption of acetyl fluxes can severely hamper their ability to form myelin leading to abnormal neuronal functionality. In this work, we explore the transcriptome of mouse oligodendrocyte precursor cells that have been silenced for Agc1 expression, reporting results of both canonical analyses such as differential expression and pathway enrichment analyses which highlight a disruption in fatty acids synthesis from both a regulatory and enzymatic stand. We further explore the transcriptome space with a network and an alternative splicing analysis: these results taken together highlight a severe alteration at the transcriptome level, which brought us to question a possible involvement of Agc1 in transcription regulation.

ORGANISM(S): Mus musculus

PROVIDER: GSE236054 | GEO | 2024/04/03

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Background: The biotechnology industry has extensively exploited Escherichia coli for producing recombinant proteins, biofuels etc. However, high growth rate aerobic E. coli cultivations are accompanied by acetate excretion i.e. overflow metabolism which is harmful as it inhibits growth, diverts valuable carbon from biomass formation and is detrimental for target product synthesis. Although overflow metabolism has been studied for decades, its regulation mechanisms still remain unclear. Results: In the current work, growth rate dependent acetate overflow metabolism of E. coli was continuously monitored using advanced continuous cultivation methods (A-stat and D-stat). The first step in acetate overflow switch (at μ = 0.27 ± 0.02 1/h) is the repression of acetyl-CoA synthethase (Acs) activity triggered by carbon catabolite repression resulting in decreased assimilation of acetate produced by phosphotransacetylase (Pta), and disruption of the PTA-ACS node. This was indicated by acetate synthesis pathways PTA-ACKA and POXB component expression down-regulation before the overflow switch at μ = 0.27 ± 0.02 1/h with concurrent 5-fold stronger repression of acetate-consuming Acs. This in turn suggests insufficient Acs activity for consuming all the acetate produced by Pta, leading to disruption of the acetate cycling process in PTA-ACS node where constant acetyl phosphate or acetate regeneration is essential for E. coli chemotaxis, proteolysis, pathogenesis etc. regulation. In addition, two-substrate A-stat and D-stat experiments showed that acetate consumption capability of E. coli decreased drastically, just as Acs expression, before the start of overflow metabolism. The second step in overflow switch is the sharp decline in cAMP production at μ = 0.45 1/h leading to total Acs inhibition and fast accumulation of acetate. Accumulation of acetate was also coupled to excretion of products such as orotate and N-carbomoyl-L-aspartate making it a novel carbon spilling mechanism in E. coli. Conclusion: This study is an example of how a systems biology approach allowed to propose a new regulation mechanism for overflow metabolism in E. coli shown by proteomic, transcriptomic and metabolomic levels coupled to two-phase acetate accumulation: acetate overflow metabolism in E. coli is triggered by Acs down-regulation resulting in decreased assimilation of acetic acid produced by Pta, and disruption of the PTA-ACS node. Reference samples at specific growth rate (μ) 0.11 1/h were compared to the ones acquired at μ 0.21, 0.26, 0.31, 0.36, 0.40 and 0.48 1/h

Dataset Information

Transcriptome-wide analysis of Agc1 downregulation in mouse oligodendrocyte precursor cells

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets