Abstract
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.
Highlights
Brown and beige adipose tissues are highly anticipated as a potential target in the treatment of obesity and its complications—including type 2 diabetes
We demonstrate that nuclear factor I-A (NFIA) activates adipogenesis and “actively” suppresses myogenesis through distinct molecular pathways to ensure brown and beige adipocyte differentiation
Dual role of NFIA to ensure brown and beige adipogenesis adipocytes derived from Nfiaflox/flox mice, we demonstrated that this domain is indispensable in order to rescue impaired beige adipogenesis caused by NFIA-knock out (KO)
Summary
Brown and beige adipose tissues are highly anticipated as a potential target in the treatment of obesity and its complications—including type 2 diabetes. Classical brown adipose tissue (BAT) and cold- or β-adrenergic stimulation-induced beige adipose tissue dissipate chemical energy in the form of heat through uncoupling protein-1 (Ucp1) on the mitochondrial inner membrane, while white adipose tissue (WAT) generally stores energy in the form of lipid. The physiological functions of brown and beige fat—including endocrine function—are currently being thoroughly investigated [1]. NFIA binds to and activates the brown-fat-specific enhancers even before differentiation and later facilitates the binding of PPARγ (peroxisome proliferator-activated receptor γ—a master transcription factor of adipogenesis), to control the brown fat gene program. In human brown and beige adipose tissue, expression levels of NFIA and the brown-fat-specific genes including UCP1 are positively correlated
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