NFIA differentially controls adipogenic and myogenic gene program through distinct pathways to ensure brown and beige adipocyte differentiation
Autoři:
Yuta Hiraike aff001; Hironori Waki aff001; Kana Miyake aff001; Takahito Wada aff001; Misato Oguchi aff001; Kaede Saito aff001; Shuichi Tsutsumi aff002; Hiroyuki Aburatani aff002; Toshimasa Yamauchi aff001; Takashi Kadowaki aff001
Působiště autorů:
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
aff001; Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
aff002; Department of Diabetes and Lifestyle-Related diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
aff003; Toranomon Hospital, Tokyo, Japan
aff004
Vyšlo v časopise:
NFIA differentially controls adipogenic and myogenic gene program through distinct pathways to ensure brown and beige adipocyte differentiation. PLoS Genet 16(9): e32767. doi:10.1371/journal.pgen.1009044
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pgen.1009044
Souhrn
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.
Klíčová slova:
Adipocyte differentiation – Adipocytes – Gene expression – Chromatin – Muscle differentiation – Proline – Transcription factors – Transcriptional control
Zdroje
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PLOS Genetics
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