Obesity-associated variants within FTO form long-range functional connections with IRX3
By Scott Smemo, J. Tena, Kyoung-Han Kim, E. Gamazon, N. Sakabe, Carlos Gómez-Marín, I. Aneas, Flavia L. Credidio, Débora R. Sobreira, N. Wasserman and 15 more. Nature, 2014
601 citations recorded by the source corpus.
Genome-wide association studies (GWAS) have reproducibly associated variants within introns of FTO with increased risk for obesity and type 2 diabetes (T2D). Although the molecular mechanisms linking these noncoding variants with obesity are not immediately obvious, subsequent studies in mice demonstrated that FTO expression levels influence body mass and composition phenotypes. However, no direct connection between the obesity-associated variants and FTO expression or function has been made. Here we show that the obesity-associated noncoding sequences within FTO are functionally connected, at megabase distances, with the homeobox gene IRX3. The obesity-associated FTO region directly interacts with the promoters of IRX3 as well as FTO in the human, mouse and zebrafish genomes. Furthermore, long-range enhancers within this region recapitulate aspects of IRX3 expression, suggesting that the obesity-associated interval belongs to the regulatory landscape of IRX3. Consistent with this, obesity-associated single nucleotide polymorphisms are associated with expression of IRX3, but not FTO, in human brains. A direct link between IRX3 expression and regulation of body mass and composition is demonstrated by a reduction in body weight of 25 to 30% in Irx3-deficient mice, primarily through the loss of fat mass and increase in basal metabolic rate with browning of white adipose tissue. Finally, hypothalamic expression of a dominant-negative form of Irx3 reproduces the metabolic phenotypes of Irx3-deficient mice. Our data suggest that IRX3 is a functional long-range target of obesity-associated variants within FTO and represents a novel determinant of body mass and composition.
Subfields: Cancer Research, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/e523a83fb2161df7f4ab31553114ba22d4a66347
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Citations in the corpus
- Detection and interpretation of shared genetic influences on 42 human traits (2016, neutral): “Regulatory variants in an intron of the FTO gene 49;50 that are associated with breast size in women (Supplementary Figure 12: rs1421085 s.d., P = 3.5 × 10 −7 ) and age at voice drop in men ( s.d., P = 2.7 × 10 −5 ), among others.”
- A Compendium of Chromatin Contact Maps Reveal Spatially Active Regions in the Human Genome (2016, neutral): “The presence of deleterious variants has been shown to mediate the expression of distal genes and confer pathology through DNA looping (Smemo et al., 2014).”
- Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets (2016, background): “2 and Table 1 ), of which 202 genes passed the experiment-wise significance threshold ( P SMR 1.7 × 10 −6 ).”
- Regulation of disease-associated gene expression in the 3D genome (2016, neutral): “Variants in introns of FTO , a gene that can influence body mass in mice 148 , were found to be located within enhancers that regulate not FTO but the physically contacted IRX3 and IRX5 genes, ~0.5–1 Mb away from the identified variants 149,150 .”