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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE83762 | GEO | 2017/08/14

SECONDARY ACCESSION(S): PRJNA326940

REPOSITORIES: GEO

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

Project description: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, PPARgamma, co-localize at the brown-fat-specific enhancers. Moreover, the binding of NFIA precedes and facilitates the binding of PPARgamma, 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 PPARg at cell-type-specific enhancers.

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NFIA in adipocytes reciprocally regulates mitochondrial and inflammatory gene program to improve glucose homeostasis [ChIP-seq]

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PPARg agonists induce a white-to-brown fat conversion through stabilization of PRDM16 protein

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NFIA differentially controls adipogenic and myogenic gene program through distinct pathways to ensure adipocyte differentiation [ingSVF RNA-seq]

Project description: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 named pro#3 domain) is required for transcriptional activity of NFIA. Full-length NFIA, but not deletion mutant lacking pro#3 domain rescued impaired Pparg expression and adipogenesis in NFIA-knockout cells. Mechanistically, the ability of NFIA to increase chromatin accessibility is mediated through pro#3 domain. However, the deletion mutant still binds to Myod1 enhancer to decrease chromatin accessibility and represses Myod1 as well as proximally transcribed non-coding RNA called DRReRNA, leading to suppression of myogenic gene program. Therefore, the negative effect of NFIA on myogenic gene program is, at least in part, independent from the positive effect on Pparg expression and its downstream adipogenic gene program. These results uncover multiple ways of action of NFIA to ensure optimal regulation of brown adipocyte differentiation.

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NFIA differentially controls adipogenic and myogenic gene program through distinct pathways to ensure adipocyte differentiation [RNA-seq]

Project description:The transcription factor nuclear factor I-A (NFIA) is a regulator of brown adipocyte differentiation. Here we show that the most C-terminal 17 amino acid residues of NFIA (which we named pro#3 domain) is required for transcriptional activity of NFIA. Full-length NFIA, but not deletion mutant lacking pro#3 domain rescued impaired Pparg expression and adipogenesis in NFIA-knockout cells. Mechanistically, the ability of NFIA to increase chromatin accessibility is mediated through pro#3 domain. However, the deletion mutant still binds to Myod1 enhancer to decrease chromatin accessibility and represses Myod1 as well as proximally transcribed non-coding RNA called DRReRNA, leading to suppression of myogenic gene program. Therefore, the negative effect of NFIA on myogenic gene program is, at least in part, independent from the positive effect on Pparg expression and its downstream adipogenic gene program. These results uncover multiple ways of action of NFIA to ensure optimal regulation of brown adipocyte differentiation.

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