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Cyclin C regulates adipogenesis by stimulating transcriptional activity of CCAAT/enhancer-binding protein ?.

ABSTRACT: Brown adipose tissue is important for maintaining energy homeostasis and adaptive thermogenesis in rodents and humans. As disorders arising from dysregulated energy metabolism, such as obesity and metabolic diseases, have increased, so has interest in the molecular mechanisms of adipocyte biology. Using a functional screen, we identified cyclin C (CycC), a conserved subunit of the Mediator complex, as a novel regulator for brown adipocyte formation. siRNA-mediated CycC knockdown (KD) in brown preadipocytes impaired the early transcriptional program of differentiation, and genetic KO of CycC completely blocked the differentiation process. RNA sequencing analyses of CycC-KD revealed a critical role of CycC in activating genes co-regulated by peroxisome proliferator activated receptor ? (PPAR?) and CCAAT/enhancer-binding protein ? (C/EBP?). Overexpression of PPAR?2 or addition of the PPAR? ligand rosiglitazone rescued the defects in CycC-KO brown preadipocytes and efficiently activated the PPAR?-responsive promoters in both WT and CycC-KO cells, suggesting that CycC is not essential for PPAR? transcriptional activity. In contrast, CycC-KO significantly reduced C/EBP?-dependent gene expression. Unlike for PPAR?, overexpression of C/EBP? could not induce C/EBP? target gene expression in CycC-KO cells or rescue the CycC-KO defects in brown adipogenesis, suggesting that CycC is essential for C/EBP?-mediated gene activation. CycC physically interacted with C/EBP?, and this interaction was required for C/EBP? transactivation domain activity. Consistent with the role of C/EBP? in white adipogenesis, CycC-KD also inhibited differentiation of 3T3-L1 cells into white adipocytes. Together, these data indicate that CycC activates adipogenesis in part by stimulating the transcriptional activity of C/EBP?.

SUBMITTER: Song Z

PROVIDER: S-EPMC5448125 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Cyclin C regulates adipogenesis by stimulating transcriptional activity of CCAAT/enhancer-binding protein α.

Song Ziyi Z Xiaoli Alus M AM Zhang Quanwei Q Zhang Yi Y Yang Ellen S T EST Wang Sven S Chang Rui R Zhang Zhengdong D ZD Yang Gongshe G Strich Randy R Pessin Jeffrey E JE Yang Fajun F

The Journal of biological chemistry 20170328 21

Brown adipose tissue is important for maintaining energy homeostasis and adaptive thermogenesis in rodents and humans. As disorders arising from dysregulated energy metabolism, such as obesity and metabolic diseases, have increased, so has interest in the molecular mechanisms of adipocyte biology. Using a functional screen, we identified cyclin C (CycC), a conserved subunit of the Mediator complex, as a novel regulator for brown adipocyte formation. siRNA-mediated CycC knockdown (KD) in brown pr ...[more]

PMID: 28351837

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Project description:α-Synuclein is the main component of Lewy bodies, the intracellular protein aggregates representing the histological hallmark of Parkinson's disease. Elevated α-synuclein levels and mutations in SNCA gene are associated with increased risk for Parkinson's disease. Despite this, little is known about the molecular mechanisms regulating SNCA transcription. CCAAT/enhancer binding protein (C/EBP) β and δ are b-zip transcription factors that play distinct roles in neurons and glial cells. C/EBPβ overexpression increases SNCA expression in neuroblastoma cells and putative C/EBPβ and δ binding sites are present in the SNCA genomic region suggesting that these proteins could regulate SNCA transcription. Based on these premises, the goal of this study was to determine if C/EBPβ and δ regulate the expression of SNCA. We first observed that α-synuclein CNS expression was not affected by C/EBPβ deficiency but it was markedly increased in C/EBPδ-deficient mice. This prompted us to characterize further the role of C/EBPδ in SNCA transcription. C/EBPδ absence led to the in vivo increase of α-synuclein in all brain regions analyzed, both at mRNA and protein level, and in primary neuronal cultures. In agreement with this, CEBPD overexpression in neuroblastoma cells and in primary neuronal cultures markedly reduced SNCA expression. ChIP experiments demonstrated C/EBPδ binding to the SNCA genomic region of mice and humans and luciferase experiments showed decreased expression of a reporter gene attributable to C/EBPδ binding to the SNCA promoter. Finally, decreased CEBPD expression was observed in the substantia nigra and in iPSC-derived dopaminergic neurons from Parkinson patients resulting in a significant negative correlation between SNCA and CEBPD levels. This study points to C/EBPδ as an important repressor of SNCA transcription and suggests that reduced C/EBPδ neuronal levels could be a pathogenic factor in Parkinson's disease and other synucleinopathies and C/EBPδ activity a potential pharmacological target for these neurological disorders.

Dataset Information

Cyclin C regulates adipogenesis by stimulating transcriptional activity of CCAAT/enhancer-binding protein ?.

Publications

Cyclin C regulates adipogenesis by stimulating transcriptional activity of CCAAT/enhancer-binding protein α.

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