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Systematic mapping of genetic interactions for de novo fatty acid synthesis identifies C12orf49 as a regulator of lipid metabolism [RNA-Seq]

ABSTRACT: The de novo synthesis of fatty acids has emerged as a therapeutic target for various diseases including cancer. Since cancer cells are intrinsically buffered to combat metabolic stress, it is important to understand how cells may adapt to loss of de novo fatty acid biosynthesis. Here we use pooled genome-wide CRISPR screens to systematically map genetic interactions (GIs) in human HAP1 cells carrying a loss-of-function mutation in FASN, which catalyzes the formation of long-chain fatty acids. FASN mutant cells show a strong dependence on lipid uptake that is reflected by negative GIs with genes involved in the LDL receptor pathway, vesicle trafficking, and protein glycosylation. Further support for these functional relationships is derived from additional GI screens in query cell lines deficient for other genes involved in lipid metabolism, including LDLR, SREBF1, SREBF2, ACACA. Our GI profiles also identify a potential role for the previously uncharacterized gene LUR1/C12orf49 in exogenous lipid uptake regulation through modulation of SREBF2 signalling in response to lipid starvation. Overall, our data highlight the genetic determinants underlying the cellular adaptation associated with loss of de novo fatty acid synthesis and demonstrate the power of systematic GI mapping for uncovering metabolic buffering mechanisms in human cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE147770 | GEO | 2020/04/30

REPOSITORIES: GEO

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Systematic mapping of genetic interactions for de novo fatty acid synthesis identifies C12orf49 as a regulator of lipid metabolism [CRISPR]

Project description:The de novo synthesis of fatty acids has emerged as a therapeutic target for various diseases including cancer. Since cancer cells are intrinsically buffered to combat metabolic stress, it is important to understand how cells may adapt to loss of de novo fatty acid biosynthesis. Here we use pooled genome-wide CRISPR screens to systematically map genetic interactions (GIs) in human HAP1 cells carrying a loss-of-function mutation in FASN, which catalyzes the formation of long-chain fatty acids. FASN mutant cells show a strong dependence on lipid uptake that is reflected by negative GIs with genes involved in the LDL receptor pathway, vesicle trafficking, and protein glycosylation. Further support for these functional relationships is derived from additional GI screens in query cell lines deficient for other genes involved in lipid metabolism, including LDLR, SREBF1, SREBF2, ACACA. Our GI profiles also identify a potential role for the previously uncharacterized gene LUR1/C12orf49 in exogenous lipid uptake regulation through modulation of SREBF2 signalling in response to lipid starvation. Overall, our data highlight the genetic determinants underlying the cellular adaptation associated with loss of de novo fatty acid synthesis and demonstrate the power of systematic GI mapping for uncovering metabolic buffering mechanisms in human cells.

2020-04-30 | GSE148627 | GEO

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Genome-wide analysis of fatty acid synthase (FASN) gene silenced normal liver cells (THLE 2) using cDNA microarray analysis

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FASN-dependent de novo lipogenesis is required for brain development

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Metabolic control of adult neural stem cell activity by FASN-dependent lipogenesis

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Genome-wide analysis of fatty acid synthase (FASN) gene silenced normal liver cells (THLE 2) using cDNA microarray analysis

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Gene expression analysis of H1299 cells in response to the presence or absence of glutamine or glucose

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