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

Nature Metabolism
Michael AreggerJason Moffat

Abstract

The de novo synthesis of fatty acids has emerged as a therapeutic target for various diseases, including cancer. Because cancer cells are intrinsically buffered to combat metabolic stress, it is important to understand how cells may adapt to the 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 fatty acid synthase (FASN), whose product catalyses the formation of long-chain fatty acids. FASN-mutant cells show a strong dependence on lipid uptake that is reflected in 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 in other genes involved in lipid metabolism, including LDLR, SREBF1, SREBF2 and ACACA. Our GI profiles also identify a potential role for the previously uncharacterized gene C12orf49 (which we call LUR1) in regulation of exogenous lipid uptake through modulation of SREBF2 signalling in response to lipid starvation. Overall, our data highlight the genetic determinants underlying the cellular adaptatio...Continue Reading

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Citations

Jul 23, 2020·Nature Metabolism·Enrico Girardi, Giulio Superti-Furga
Feb 15, 2021·Experimental Cell Research·Yusuke SekineShiori Sekine
May 22, 2021·Molecular Systems Biology·Mahfuzur RahmanChad L Myers
Jun 3, 2021·International Journal of Molecular Sciences·Mayra ColardoMarco Segatto
Sep 1, 2021·Life Science Alliance·Melanie L BaileyPhilip Hieter
Sep 12, 2021·Nature Protocols·Henry N WardChad L Myers

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Methods Mentioned

BETA
Illumina sequencing
glycosylation
nuclear translocation
that
protein modification
reverse-transcription PCR
PCR
transfection
Assay
X‐ray

Clinical Trials Mentioned

NCT02223247
NCT02948569
NCT03179904
NCT02980029

Software Mentioned

Proteomic Pipeline ( TPP
STAR short aligner
iProphet
HumanCyc
Comet
Cytoscape Enrichment Map
STAR
Bioconductor
gProfileR R package
AutoAnnotate

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