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Far Away but Never Lost Control
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The name of the fat mass and obesity-associated protein (FTO) seems to tell an obvious story about mammalians’ over-weight problem. For a long time, scientists have correlated the dysregulated function of FTO to the risk of metabolic disorder and obesity. Recently, multiple non-coding germline variants, which sit in the intronic enhancer regions of FTO, were suspected to mediate FTO expression directly, and thus they influenced the obesity-related pathways. However, contradictory to this prediction, the FTO gene is universally expressed in mice under the control of a strong promoter. Is there a reason for the presence of these regulatory mutations in the host genome?


On September 15th, 2014, Dr. Marcelo Nobrega from the University of Chicago delivered a talk about “Regulatory Variation and Human Diseases” at Beijing Institute of Genomics (BIG), Chinese Academy of Sciences. He presented recent discoveries (Nature 507, 371-375, doi:10.1038/nature13138, 2014) in his lab to the students and faculty members. Dr. Nobrega’s team took advantage of the findings from the Genome-wide association study (GWAS) to identify FTO polygenetic germline variations, and they attempted to link these variations to human diseases, such as obesity. In addition to chromosome conformation capture sequencing (3C-sequencing), they also employed technically challenging 4C strategy (Circular chromosome conformation capture sequencing) to identify distant target genes of regulatory enhancer in the FTO introns and found the target gene of IRX3. With a clear regulatory landscape of IRX3 derived from eQTL analysis, they showed for the first time that enhancers residing in the FTO intron regions serve as trans-regulators (far-away from the target gene) which regulate IRX3 expression.


They further identified the role of IRX3 in body fat metabolism by using a series of mutagenesis studies: IRX3 may be related to the fate determination of white or brown adipose tissue, which are responsible for the storing and burning of fat, respectively. These findings are important for the understanding of metabolic abnormality in humans and provided a success example for the functional significance of non-coding regulatory variations in the human genome.


Dr. Nobrega passionately discussed his research with the BIG students and faculty members in the following Q&A section. They talked about the implications of the study, more backstage stories, and exchanged ideas about future directions. Dr. Nobrega is a tenured associate professor at the Department of Human Genetics, Committee on Systems Biology and Genomics, University of Chicago. He was hosted by Dr. WANG Qianfei from BIG, CAS. Dr. Nobrega and Dr. WANG were colleagues at the Genome Science Division, Lawrence Berkeley National Laboratory at UC Berkeley during their postdoctoral fellow training in early 2000’s. As part of the joined research efforts between BIG and the University of Chicago, they have developed a close collaboration on the study of gene regulation and human diseases.