Editors' ChoiceOBESITY GENOMICS

A brite idea for noncoding variants

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Science Translational Medicine  02 Sep 2015:
Vol. 7, Issue 303, pp. 303ec152
DOI: 10.1126/scitranslmed.aad1831

Obesity has a strong genetic component of 40 to 80% heritability, and genome-wide association studies (GWAS) have revealed the existence of obesity-associated regions in the human genome. However, the majority of signals from GWAS are noncoding variants, and the role of noncoding variants is challenging to interpret. To give meaning to variants that may increase the risk of being obese, Claussnitzer et al. performed a combined epigenomic and genomics analysis to find targets of the FTO risk genotype, which has been shown to have the strongest association with obesity. The authors combined results from ChIP-seq, chromatin conformation capture, and comparative genomic analyses to find the targets of the risk genotype. Their analysis demonstrated that the causal variant of the FTO risk genotype disrupts the binding of ARID5B, a repressor of the region, resulting in a gain of enhancer activity and increased expression of the genes IRX3 and IRX5. Owing to their role in thermogenesis, an increase in IRX3 and IRX5 led to a change in the behavior of fat cells: Adipocytes went from active, energy-dissipating “beige (brite)” cells, to fat-storing “white” cells. Blocking the activity of Irx3 in adipose tissue in mice returned the animals’ weight to normal. Furthermore, repairing the risk allele in human adipocytes with the CRISPR-Cas9 genome-editing technique, the authors rescued the cells’ obese phenotype and negated the risky genotype. Other than elucidating the mechanism of noncoding FTO obesity variants, this study shows how both epigenomic and genomic information can be combined with gene-editing technologies to develop therapeutic approaches to challenging metabolic and genetic diseases, including obesity.

M. Claussnitzer et al., FTO obesity variant circuitry and adipocyte browning in humans. N. Engl. J. Med. 10.1056/NEJMoa1502214 (2015). [Abstract]

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