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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

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

Project description:Mechanisms controlling the proliferative activity of neural stem/progenitor cells (NSPCs) play a pivotal role to ensure life-long neurogenesis in the mammalian brain. How metabolic programs are coupled with NSPC activity remains unknown. Here we show that fatty acid synthase (FASN), the key enzyme of de novo lipogenesis, is highly active in adult NSPCs and that conditional deletion of FASN in NSPCs impairs adult neurogenesis. The rate of de novo lipid synthesis and subsequent proliferation of NSPCs is regulated by Spot14, a gene we found to be selectively expressed in low proliferating adult NSPCs. Spot14 reduces the availability of malonyl-CoA, which is an essential substrate for FASN to fuel lipogenesis. Thus, we here identified a functional coupling between the regulation of lipid metabolism and adult NSPC proliferation. 6 samples were analyzed. Spot14+: Spot14 GFP positive mouse neural stem cell, 3 biological rep Spot14-: Spot14 GFP negative mouse neural stem cell, 3 biological rep

2012-11-02 | E-GEOD-27391 | biostudies-arrayexpress

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

Project description:Fatty acid synthase is a major enzyme involved in de novo lipogenesis, associated with energy homeostasis, lipid storage and signalling in normal liver cells. The effect of fatty acid synthase knockdown in normal liver cells (THLE 2) using siRNA mediated gene silencing were assesed for global gene deregulations. The deregulated metabolism, cell signalling and cell cycle pathway related gene expressions were analysed. Statistical significance values were also recorded. This expermental analysis clearly points to a important biochemical role for FASN in normal liver cell physiology. Total RNA was extracted from the THLE 2 cells transfected with FASN siRNA at 48h, along with its untransfected control cells. cDNA converted samples were run on microarray platform- Illumina HumanHT-12 V4.0 expression beadchip

2016-06-02 | E-GEOD-82096 | biostudies-arrayexpress

FASN-dependent de novo lipogenesis is required for brain development

Project description:Fate and behaviour of neural progenitor cells is tightly regulated during mammalian brain development. Metabolic pathways, such as glycolysis and oxidative phosphorylation, that are required for supplying energy and providing molecular building blocks to generate cells, govern progenitor function. However, the role of de novo lipogenesis, which is the conversion of glucose into fatty acids through the multi-enzyme protein fatty acid synthase (FASN), for brain development remains unknown. Using Emx1Cre-mediated, tissue-specific deletion of Fasn in the mouse embryonic telencephalon, we show that loss of FASN causes severe microcephaly, largely due to altered polarity of apical, radial glia progenitors (APs) and reduced progenitor proliferation. Further, genetic deletion and pharmacological inhibition of FASN in human embryonic stem cell (ESC)-derived forebrain organoids identifies a conserved role of FASN-dependent lipogenesis for radial glia cell polarity and progenitor expansion in the developing human forebrain. Thus, our data establish a role of de novo lipogenesis for mouse and human brain development and identify a link between progenitor cell polarity and lipid metabolism.

2022-01-14 | PXD026110 | Pride

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

2012-11-02 | GSE27391 | GEO

Fatty acid synthesis suppresses dietary polyunsaturated fatty acid use

Project description:Metabolic diseases are closely linked to aberrant synthesis of endogenous fatty acids in the liver, called de novo lipogenesis (DNL), which is mediated by the enzyme fatty acid synthase (FASN). The composition of complex lipids consists of saturated or monosaturated fatty acids, which can be endogenously produced, and polyunsaturated fatty acids (PUFA), which are strictly dietary. Compositional differences between individuals are insufficiently understood and may influence the onset and progression of metabolic and cardiovascular diseases. Here we show that DNL critically determines the use of dietary PUFA. A patient with a hypofunctional heterozygous de novo Arg2177Cys variant in FASN exhibited an elevated composition of PUFA, which was phenocopied by pharmacological inhibition of FASN with TVB-2640 in patients with nonalcoholic steatohepatitis (NASH). In mice, the incorporation rate of supplemented omega-3 PUFA during an obesogenic diet was increased by genetic or pharmacologic reduction of DNL. Mechanistically, we show that the FASN variant exhibited a cysteine-dependent, non-enzymatic acetylation of FASN, which resulted in hyperubiquitinylation and decreased protein stability. Our study further reveals that PUFA storage is an active, enzymatic process controlled by FASN, diacylglycerol O-acyltransferase 2 (DGAT2) and MFSD2A, a membrane-transport protein, and that combining FASN inhibition and PUFA supplementation exerts additive beneficial metabolic effects. These findings provide evidence that the success of PUFA supplementation may depend on the rate of endogenous DNL and that combined PUFA supplementation and FASN inhibition may be a promising approach targeting metabolic disease.

2023-12-19 | PXD045908 | Pride

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

2016-06-02 | GSE82096 | GEO

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

Project description:By a transcriptome analysis using RNA sequencing in H1299 cells, a non-small cell lung cancer cell line (NSCLC), we determined the response of lipogenic genes to absence vs. presence of glutamine (Gln) or glucose (Gluc). We found that neither glutamine nor glucose alone was able to activate the expression of genes regulating fatty acid and cholesterol synthesis, and uptake, including SREBF1, SREBF2, ACLY, ACACA, FASN, SCD1, HMGCR and LDLR, as compared to absence of both. And, activation of lipogenic genes required the presence of both glutamine and glucose, but SCAP gene expression was not affected by either glutamine or glucose. The RNA sequencing analysis in H1299 cells also confirmed that ammonia, similarly to glutamine, significantly activated the expression of genes controlling the fatty acid and cholesterol synthesis pathways as compared to glucose alone. This study detemines the intrinsic molecular connection between glutamine, glucose and lipid synthesis.

2022-04-30 | GSE199089 | GEO

Elevated dairy fat intake in lactating women alters milk lipid and fatty acids without detectible changes in expression of genes related to lipid uptake or synthesis

Project description:Previous work has demonstrated that elevated maternal lipid intake (particularly from dairy products) is associated with increased lipids and altered fatty acid profile in milk produced by healthy lactating women. We investigate our primary hypothesis that a maternal diet rich in full-fat dairy products would simultaneously increase milk lipid percent and expression of genes related to the uptake and/or de novo biosynthesis of milk lipids.

2015-02-24 | GSE66191 | GEO

Transcriptomic analysis of the peripheral nervous system of Schwann cell-conditional FASN knockout mice

Project description:Myelination calls for a tremendous surge in cell metabolism towards lipids and membrane production. However, functional relevance of de novo fatty acid synthesis in myelinating cells remains unclear. We generated mutant mice in which the enzyme fatty acid synthase (FASN) was depleted conditionally in Schwann cells, the myelinating glial cells of the peripheral nervous system. To address how lack of FASN was affecting the development of the peripheral nervous system, we screened with an Affymetrix Transcriptomic approach the transcriptome of sciatic nerves and roots of P60 FASN mutant mice, comparing to control mice.

2018-02-02 | GSE71373 | GEO

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