NFIA differentially controls adipogenic and myogenic gene program through distinct pathways to ensure brown and beige adipocyte differentiation

Yuta Hiraike; Hironori Waki; Kana Miyake; Takahito Wada; Misato Oguchi; Kaede Saito; Shuichi Tsutsumi; Hiroyuki Aburatani; Toshimasa Yamauchi; Takashi Kadowaki

doi:10.1371/journal.pgen.1009044

NFIA differentially controls adipogenic and myogenic gene program through distinct pathways to ensure brown and beige adipocyte differentiation

PLoS Genet. 2020 Sep 29;16(9):e1009044. doi: 10.1371/journal.pgen.1009044. eCollection 2020 Sep.

Authors

Affiliations

¹ Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
² Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
³ Department of Diabetes and Lifestyle-Related diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
⁴ Toranomon Hospital, Tokyo, Japan.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adipocytes, Beige / cytology*
Adipocytes, Beige / physiology
Adipocytes, Brown / cytology*
Adipocytes, Brown / physiology
Adipogenesis / genetics
Adipogenesis / physiology*
Animals
Cell Differentiation / genetics
Chromatin / genetics
Chromatin / metabolism
Gene Expression Regulation
HEK293 Cells
Humans
Mice, Inbred C57BL
Mice, Knockout
Muscle Development / genetics
Muscle Development / physiology*
MyoD Protein / genetics
Myogenin / genetics
NFI Transcription Factors / genetics
NFI Transcription Factors / metabolism*
PPAR gamma / genetics
PPAR gamma / metabolism
Proline
Protein Domains

Substances

Chromatin
MyoD Protein
MyoD1 myogenic differentiation protein
Myog protein, mouse
Myogenin
NFI Transcription Factors
Nfia protein, mouse
PPAR gamma
Pparg protein, mouse
Proline

Grants and funding

This work is funded by an AMED-CREST research grant from the Japan Agency for Medical Research and Development (AMED), grant number JP18gm0510018 to T.Y.; by a junior scientist development grant from the Japan Diabetes Society to Y.H.; by a grant for front runner of future diabetes research (FFDR) from the Japan foundation for applied enzymology, grant number 17F005 to Y.H.; by JSPS KAKENHI Grant-in-Aid for Scientific Research (C), grant number 17K09818 and by JSPS KAKENHI Grant-in-Aid for Scientific Research (B), grant number 20H04101 to H.W.; by a grant from the Cell Science Research Foundation to H.W.; by a grant from Takeda Science Foundation to H.W. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.