부산대학교 도서관

The transcription factor nuclear factor I-A (NFIA) is a regulator of brown adipocyte differentiation. Here we show that the C-terminal 17 amino acid residues of NFIA (which we call pro#3 domain) are required for the transcriptional activity of NFIA. Full-length NFIA—but not deletion mutant lacking pro#3 domain—rescued impaired expression of PPARγ, the master transcriptional regulator of adipogenesis and impaired adipocyte differentiation in NFIA-knockout cells. Mechanistically, the ability of NFIA to penetrate chromatin and bind to the crucial Pparg enhancer is mediated through pro#3 domain. However, the deletion mutant still binds to Myod1 enhancer to repress expression of MyoD, the master transcriptional regulator of myogenesis as well as proximally transcribed non-coding RNA called DRReRNA, via competition with KLF5 in terms of enhancer binding, leading to suppression of myogenic gene program. Therefore, the negative effect of NFIA on the myogenic gene program is, at least partly, independent of the positive effect on PPARγ expression and its downstream adipogenic gene program. These results uncover multiple ways of action of NFIA to ensure optimal regulation of brown and beige adipocyte differentiation. Author summary: Obesity and its complications including type 2 diabetes are growing concerns worldwide. While white adipocytes generally store energy in the form of lipid, classical brown and cold- or β-adrenergic stimulation-induced beige adipocytes dissipate chemical energy in the form of heat through uncoupling protein-1 (Ucp1). Since the re-discovery of human brown and beige adipocytes, it has been considered a promising target for the treatment of obesity. During mesenchymal development, not only activation of brown/beige adipocyte gene program but also repression of muscle gene program is required to achieve thermogenic adipocyte differentiation. Previously, we identified the transcription factor nuclear factor I-A (NFIA) as a regulator of brown adipocyte differentiation. Here we show that the C-terminal 17 amino acid residues of NFIA, which we call pro#3 domain, is required for activation of adipocyte differentiation. However, the deletion mutant which lacks this domain is still able to suppress muscle gene program by repressing the expression of Myod1, which encode the master transcriptional regulator of myogenesis, MyoD. We demonstrate that NFIA activates adipogenesis and also "actively" suppresses myogenesis through distinct molecular pathways to ensure brown and beige adipocyte differentiation. [ABSTRACT FROM AUTHOR]