TF and obesity due to melanocortin 4 receptor deficiency: Through analysis of inherent bHLH-PAS heterodimer response element specificity, in vivo chromatin occupancy and DNA methylation patterns, DNA shape-affinity relationships, protein–DNA structural analysis, and a novel Sim1R171H knock-in mouse model of obesity, we reveal mechanisms underlying target specificity of the bHLH-PAS TF family.