Identification of a weight loss-associated causal eQTL inMTIF3and the effects ofMTIF3deficiency on human adipocyte function
Abstract
Background
Genetic variation at theMTIF3(Mitochondrial Translational Initiation Factor 3) locus has been robustly associated with obesity in humans, but the functional basis behind this association is not known.
Methods
Here, we applied luciferase reporter assay to map potential functional variants in the haplotype block tagged by rs1885988 and used CRISPR-Cas9 to edit the potential functional variants to confirm the regulatory effects onMTIF3expression. We further conducted functional studies on MTIF3-deficient differentiated human white adipocyte cell line (hWAs-iCas9), generated through inducible expression of CRISPR-Cas9 combined with delivery of syntheticMTIF3-targeting guide RNA.
Results
We demonstrate that rs67785913-centered DNA fragment (in LD with rs1885988, r2>0.8) enhances transcription in a luciferase reporter assay, and CRISPR/Cas9 edited rs67785913 CTCT cells show significantly higherMTIF3expression than rs67785913 CT cells. PerturbedMTIF3expression changed the expression of mitochondrial DNA-encoded genes, and reduced mitochondrial respiration, as well as altered endogenous fatty acid oxidation. Furthermore, after glucose restriction, theMTIF3knockout cells retained more triglycerides than control cells.
Conclusions
This study demonstrates an adipocyte function-specific role ofMTIF3, which originates in the maintenance of mitochondrial function, providing potential explanations for whyMTIF3genetic variation at rs67785913 is associated with body corpulence and response to weight loss interventions.
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