Obesity-associated variants within FTO form long-range functional connections with IRX3. Obesity-associated variants within FTO form long-range functional connections with IRX3

Genome-wide association studies in diverse populations have reproducibly associated variants within introns of FTO with increased risk for obesity and type-2 diabetes.While 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. Yet, no direct connection between the obesity-associated intronic variants and FTO expression or function has been made. We show that the obesity-associated noncoding sequences within FTO are functionally connected, at megabase distances, primarily with the homeobox gene IRX3, rather than with FTO. Overall design: 4C-seq samples for Fto/fto and Irx3/irx3a genes promoters in different samples: adult mouse brain, E9.5 mouse embryos and 24hpf zebrafish embryos.

不同人群中的全基因组关联研究（Genome-wide association studies）已可重复地将FTO基因内含子区域的变异与肥胖及2型糖尿病的发病风险升高建立关联。尽管将这些非编码变异与肥胖关联的分子机制尚不明确，后续的小鼠研究证实，FTO的表达水平会影响体重与体成分表型。然而，目前尚未明确肥胖相关内含子变异与FTO表达或功能之间的直接关联。本研究表明，FTO基因内与肥胖相关的非编码序列在兆碱基级别的距离范围内，主要与同源框基因IRX3存在功能关联，而非FTO自身。实验整体设计：针对不同样本中的Fto/fto与Irx3/irx3a基因启动子开展4C-seq测序，所用样本包括成年小鼠脑组织、E9.5期小鼠胚胎以及24hpf斑马鱼胚胎。