NFIA Controls the Brown Fat Gene Program by Co-Localizing with PPARgamma at Cell-Type-Specific Enhancers (RNA). Mus musculus

Brown fat dissipates energy as heat and protects against obesity. Here, we identified nuclear factor I-A (NFIA) as a novel transcriptional regulator of brown fat by a genome-wide open chromatin analysis of murine brown and white fat followed by motif analysis of brown-fat-specific open chromatin regions. NFIA and the adipogenic master regulator, PPARγ, co-localize at the brown-fat-specific enhancers. Moreover, the binding of NFIA precedes and facilitates the binding of PPARγ, leading to increased chromatin accessibility and active transcription. Introduction of NFIA into myoblasts results in brown adipocyte differentiation. Conversely, the brown fat of NFIA knockout mice displays impaired expression of the brown-fat-specific genes and reciprocal elevation of muscle genes. Finally, expression of NFIA and the brown-fat-specific genes is positively correlated in human brown fat. These results indicate that NFIA is a key transcriptional regulator of brown fat and exerts its effects by co-localizing with PPARγ at cell-type-specific enhancers. Overall design: RNA-seq analysis of ctrl- or NFIA-expressing C2C12 myoblasts, BAT of wild type or NFIA-KO mouse neonates.