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

Ziyi Song, Alus M. Xiaoli, Quanwei Zhang, Yi Zhang, Ellen S.T. Yang, Sven En Wang, Rui Chang, Zhengdong D. Zhang, Gongshe Yang, Randy Strich, Jeffrey E. Pessin, Fajun Yang

Research output: Contribution to journalArticle

2 Citations (Scopus)

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. RNAsequencing analyses of CycC-KD revealed a critical role of CycC in activating genes co-regulated by peroxisome proliferator activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα). Overexpression of PPARγ2 or addition of the PPARγ ligand rosiglitazone rescued the defects in CycC-KO brown preadipocytes and efficiently activated the PPARγ-responsive promoters in both WT and CycC-KO cells, suggesting that CycC is not essential for PPARγ transcriptional activity. In contrast, CycC-KO significantly reduced C/EBPα-dependent gene expression. Unlike for PPARγ, overexpression of C/EBPα could not induce C/EBPα target gene expression in CycC-KO cells or rescue the CycC-KO defects in brown adipogenesis, suggesting that CycC is essential for C/EBPα-mediated gene activation. CycC physically interacted with C/EBPα, and this interaction was required for C/EBPα transactivation domain activity. Consistent with the role of C/EBPα 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/EBPα.

Original languageEnglish (US)
Pages (from-to)8918-8932
Number of pages15
JournalJournal of Biological Chemistry
Volume292
Issue number21
DOIs
StatePublished - May 26 2017

Fingerprint

Cyclin C
CCAAT-Enhancer-Binding Proteins
Adipogenesis
Peroxisome Proliferator-Activated Receptors
rosiglitazone
Gene expression
Transcriptional Activation
Genes
Mediator Complex
White Adipocytes
Brown Adipocytes
3T3-L1 Cells
Gene Expression

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Cyclin C regulates adipogenesis by stimulating transcriptional activity of CCAAT/enhancer-binding protein α. / Song, Ziyi; Xiaoli, Alus M.; Zhang, Quanwei; Zhang, Yi; Yang, Ellen S.T.; Wang, Sven En; Chang, Rui; Zhang, Zhengdong D.; Yang, Gongshe; Strich, Randy; Pessin, Jeffrey E.; Yang, Fajun.

In: Journal of Biological Chemistry, Vol. 292, No. 21, 26.05.2017, p. 8918-8932.

Research output: Contribution to journalArticle

@article{aaea4332b72a4f9da9782f078722b9fc,
title = "Cyclin C regulates adipogenesis by stimulating transcriptional activity of CCAAT/enhancer-binding protein α",
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. RNAsequencing analyses of CycC-KD revealed a critical role of CycC in activating genes co-regulated by peroxisome proliferator activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα). Overexpression of PPARγ2 or addition of the PPARγ ligand rosiglitazone rescued the defects in CycC-KO brown preadipocytes and efficiently activated the PPARγ-responsive promoters in both WT and CycC-KO cells, suggesting that CycC is not essential for PPARγ transcriptional activity. In contrast, CycC-KO significantly reduced C/EBPα-dependent gene expression. Unlike for PPARγ, overexpression of C/EBPα could not induce C/EBPα target gene expression in CycC-KO cells or rescue the CycC-KO defects in brown adipogenesis, suggesting that CycC is essential for C/EBPα-mediated gene activation. CycC physically interacted with C/EBPα, and this interaction was required for C/EBPα transactivation domain activity. Consistent with the role of C/EBPα 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/EBPα.",
author = "Ziyi Song and Xiaoli, {Alus M.} and Quanwei Zhang and Yi Zhang and Yang, {Ellen S.T.} and Wang, {Sven En} and Rui Chang and Zhang, {Zhengdong D.} and Gongshe Yang and Randy Strich and Pessin, {Jeffrey E.} and Fajun Yang",
year = "2017",
month = "5",
day = "26",
doi = "10.1074/jbc.M117.776229",
language = "English (US)",
volume = "292",
pages = "8918--8932",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "21",

}

TY - JOUR

T1 - Cyclin C regulates adipogenesis by stimulating transcriptional activity of CCAAT/enhancer-binding protein α

AU - Song, Ziyi

AU - Xiaoli, Alus M.

AU - Zhang, Quanwei

AU - Zhang, Yi

AU - Yang, Ellen S.T.

AU - Wang, Sven En

AU - Chang, Rui

AU - Zhang, Zhengdong D.

AU - Yang, Gongshe

AU - Strich, Randy

AU - Pessin, Jeffrey E.

AU - Yang, Fajun

PY - 2017/5/26

Y1 - 2017/5/26

N2 - 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. RNAsequencing analyses of CycC-KD revealed a critical role of CycC in activating genes co-regulated by peroxisome proliferator activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα). Overexpression of PPARγ2 or addition of the PPARγ ligand rosiglitazone rescued the defects in CycC-KO brown preadipocytes and efficiently activated the PPARγ-responsive promoters in both WT and CycC-KO cells, suggesting that CycC is not essential for PPARγ transcriptional activity. In contrast, CycC-KO significantly reduced C/EBPα-dependent gene expression. Unlike for PPARγ, overexpression of C/EBPα could not induce C/EBPα target gene expression in CycC-KO cells or rescue the CycC-KO defects in brown adipogenesis, suggesting that CycC is essential for C/EBPα-mediated gene activation. CycC physically interacted with C/EBPα, and this interaction was required for C/EBPα transactivation domain activity. Consistent with the role of C/EBPα 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/EBPα.

AB - 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. RNAsequencing analyses of CycC-KD revealed a critical role of CycC in activating genes co-regulated by peroxisome proliferator activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα). Overexpression of PPARγ2 or addition of the PPARγ ligand rosiglitazone rescued the defects in CycC-KO brown preadipocytes and efficiently activated the PPARγ-responsive promoters in both WT and CycC-KO cells, suggesting that CycC is not essential for PPARγ transcriptional activity. In contrast, CycC-KO significantly reduced C/EBPα-dependent gene expression. Unlike for PPARγ, overexpression of C/EBPα could not induce C/EBPα target gene expression in CycC-KO cells or rescue the CycC-KO defects in brown adipogenesis, suggesting that CycC is essential for C/EBPα-mediated gene activation. CycC physically interacted with C/EBPα, and this interaction was required for C/EBPα transactivation domain activity. Consistent with the role of C/EBPα 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/EBPα.

UR - http://www.scopus.com/inward/record.url?scp=85019756920&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85019756920&partnerID=8YFLogxK

U2 - 10.1074/jbc.M117.776229

DO - 10.1074/jbc.M117.776229

M3 - Article

C2 - 28351837

AN - SCOPUS:85019756920

VL - 292

SP - 8918

EP - 8932

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 21

ER -