The Mediator subunit MED20 organizes the early adipogenic complex to promote development of adipose tissues and diet-induced obesity

Cell Rep. 2021 Jul 6;36(1):109314. doi: 10.1016/j.celrep.2021.109314.

Abstract

MED20 is a non-essential subunit of the transcriptional coactivator Mediator complex, but its physiological function remains largely unknown. Here, we identify MED20 as a substrate of the anti-obesity CRL4-WDTC1 E3 ubiquitin ligase complex through affinity purification and candidate screening. Overexpression of WDTC1 leads to degradation of MED20, whereas depletion of WDTC1 or CUL4A/B causes accumulation of MED20. Depleting MED20 inhibits adipogenesis, and a non-degradable MED20 mutant restores adipogenesis in WDTC1-overexpressing cells. Furthermore, knockout of Med20 in preadipocytes abolishes development of brown adipose tissues. Removing one allele of Med20 in preadipocytes protects mice from diet-induced obesity and reverses weight gain in Cul4a- or Cul4b-depleted mice. Chromatin immunoprecipitation sequencing (ChIP-seq) analysis reveals that MED20 organizes the early adipogenic complex by bridging C/EBPβ and RNA polymerase II to promote transcription of the central adipogenic factor, PPARγ. Our findings have thus uncovered a critical role of MED20 in promoting adipogenesis, development of adipose tissue and diet-induced obesity.

Keywords: C/EBPβ; CRL4; MED20; PPARγ; WDTC1; adipogenesis; adipose tissue; obesity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / metabolism
  • Adipogenesis*
  • Adipose Tissue, Brown* / metabolism
  • Alleles
  • Animals
  • Base Sequence
  • CCAAT-Enhancer-Binding Protein-beta / metabolism
  • Diet*
  • Enhancer Elements, Genetic / genetics
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Obesity* / metabolism
  • Obesity* / pathology
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Protein Subunits* / metabolism
  • Proteins / metabolism
  • Proteolysis
  • RNA Polymerase II / metabolism
  • Receptors, Interleukin-17 / metabolism
  • Substrate Specificity
  • Transcription, Genetic

Substances

  • CCAAT-Enhancer-Binding Protein-beta
  • Cebpb protein, mouse
  • Il17rb protein, mouse
  • PPAR gamma
  • Protein Subunits
  • Proteins
  • Receptors, Interleukin-17
  • RNA Polymerase II
  • Wdtc1 protein, mouse
  • Med20 protein, mouse