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

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 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE130388 | GEO | 2020/09/22

REPOSITORIES: GEO

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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.

2020-09-22 | GSE142609 | GEO

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.

2020-09-22 | GSE130389 | GEO

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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Pro-neuronal activity of Myod1 due to promiscuous binding [FLAG ChIP-seq]

Project description:Basic helix-loop-helix (bHLH) pioneer transcription factors Myod1 and Ascl1 are biochemically related but produce fundamentally different outcomes when expressed in fibroblasts: Myod1 produces muscle cells and Ascl1 induces neurons. Here, we sought to investigate the molecular mechanisms explaining the differential activity. Surprisingly, we found a large overlap in the overall binding patterns of Ascl1 and Myod1 in fibroblasts, with both transcription factors accessing both neuronal and myogenic targets. We also observed similar changes in chromatin accessibility and transcriptional activation. Yet, Myod1 predominantly induced a muscle program and Ascl1 a neuronal program. We found that differences in binding affinity at key targets resulted in largely distinct reprogramming outcomes. Accordingly, exchanging Myod1’s C-terminal protein-protein interacting domain and DNA-binding basic domain with those of Ascl1 induces an Ascl1-like binding and converts Myod1 into a pro-neuronal factor. Finally, we found that co-expression of Myod1 with the transcriptional repressor Myt1l inhibits induction of the muscle program and yields functional neuronal cells. Our findings are compatible with the notion that pioneer factor activity is associated with high-affinity protein-DNA and suggest that promiscuous binding of pioneer factors can induce unspecific lineage features which need to be kept in check by co-factor interactions.

2020-02-03 | GSE126410 | GEO

Pro-neuronal activity of Myod1 due to promiscuous binding [ATAC-seq]

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Pro-neuronal activity of Myod1 due to promiscuous binding [FLAG ChIP-seq mESC]

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Pro-neuronal activity of Myod1 due to promiscuous binding [RNA-seq]

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Pro-neuronal activity of Myod1 due to promiscuous binding [H3K27ac ChIP-seq]

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

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, 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.

2017-08-14 | GSE83762 | GEO

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

Project description:Adipose tissue is central to regulation of systemic energy homeostasis. Adaptive thermogenesis in brown and beige adipocytes, which relies on mitochondrial oxidative phosphorylation, dissipates energy to counteract obesity. On the other hand, chronic inflammation in adipose tissue is linked to insulin resistance, type 2 diabetes and obesity. Here we show that nuclear factor I-A (NFIA), a transcriptional regulator of brown and beige adipocytes, improves systemic glucose homeostasis via up-regulation of oxidative phosphorylation and reciprocal down-regulation of inflammation. Mice with transgenic expression of NFIA in adipocytes exhibited improved glucose tolerance, increased energy expenditure and limited weight gain on high fat diet. NFIA coordinately up-regulate genes involved in oxidative phosphorylation as well as a battery of brown-fat-specific genes through enhancer activation that involves facilitated genomic binding of PPARγ. In contrast, NFIA in adipocytes, but not in macrophages, down-regulate pro-inflammatory cytokine genes to ameliorate adipose tissue inflammation in vivo. NFIA binds to enhancer/promoter region of Ccl2 gene that encodes pro-inflammatory cytokine MCP-1, to down-regulate its transcription. NFIA expression and CCL2 expression was negatively correlated in human adipose tissue. These results indicate that NFIA in adipocytes reciprocally regulate mitochondrial and inflammatory gene program to improve systemic glucose homeostasis.

2023-07-25 | GSE200192 | GEO

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