1. Ashley Patton DO/PhD student McCall/Schwartz Lab

2. Background BMI has a strong genetic component Large genomewide association studies have identified a region in introns 1 and 2 of the FTO gene Goal Identify a mechanistic basis for the association of the FTO locus and obesity

3. Methods Identify a causal variant with regulatory roles Using various computational and molecular techniques Identify the upstream regulator Examined regulatory motif matches and regulator expression levels in adipocytes from obese and non-obese participants Follow by experimnetal validation by knockdown and overexpression in adipocytes from risk-allele and nonrisk-allele carriers. Identify the downstream target gene Target genes were predicted by identifying long-range 3D chromatin interactions surrounding the FTO locus IRX3 and IRX5 genotype-associated expression and long-range control in primary preadipocytes Identified the biological processes affected by altered IRX3 and IRX5 expression in adipocytes: Mitochondrial Thermogenesis Lipid Storage Results Identified a pathway for adipocyte thermogenesis regulation involving ARID5B, rs1421085, IRX3, and IRX5, which when manipulated, had pronounced pro-obesity and anti-obesity effects.