4.6 Article

Transcriptome and metabolome analysis of crGART, a novel cell model of de novo purine synthesis deficiency: Alterations in CD36 expression and activity

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PLOS ONE
卷 16, 期 7, 页码 -

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PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0247227

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  1. Itkin Foundation
  2. Sam and Frieda Davis Trust
  3. Butler Family Fund of the Denver Foundation
  4. Lowe Fund of the Denver Foundation

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This study characterized the transcriptomes of crGART and HeLa cells under purine-supplemented and purine-depleted conditions, revealing multiple transcriptome changes and pathways relevant to Alzheimer's disease and Down syndrome. The differential expression of the CD36 gene in crGART highlighted its importance in the context of GART activity deficiency.
In humans, GART [phosphoribosylglycinamide formyltransferase (EC 2.1.2.2) / phosphoribosylglycinamide synthetase (EC 6.3.4.13) / phosphoribosylaminoimidazole synthetase (EC 6.3.3.1)] is a trifunctional protein which catalyzes the second, third, and fifth reactions of the ten step de novo purine synthesis (DNPS) pathway. The second step of DNPS is conversion of phosphoribosylamine (5-PRA) to glycineamide ribonucleotide (GAR). 5-PRA is extremely unstable under physiological conditions and is unlikely to accumulate in the absence of GART activity. Recently, a HeLa cell line null mutant for GART was constructed via CRISPR-Cas9 mutagenesis. This cell line, crGART, is an important cellular model of DNPS inactivation that does not accumulate DNPS pathway intermediates. In the current study, we characterized the crGART versus HeLa transcriptomes in purine-supplemented and purine-depleted growth conditions. We observed multiple transcriptome changes and discuss pathways and ontologies particularly relevant to Alzheimer disease and Down syndrome. We selected the Cluster of Differentiation (CD36) gene for initial analysis based on its elevated expression in crGART versus HeLa as well as its high basal expression, high log2 value, and minimal P-value.

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