Mediator complex interaction partners organize the transcriptional network that defines neural stem cells

Nat Commun. 2019 Jun 17;10(1):2669. doi: 10.1038/s41467-019-10502-8.


The Mediator complex regulates transcription by connecting enhancers to promoters. High Mediator binding density defines super enhancers, which regulate cell-identity genes and oncogenes. Protein interactions of Mediator may explain its role in these processes but have not been identified comprehensively. Here, we purify Mediator from neural stem cells (NSCs) and identify 75 protein-protein interaction partners. We identify super enhancers in NSCs and show that Mediator-interacting chromatin modifiers colocalize with Mediator at enhancers and super enhancers. Transcription factor families with high affinity for Mediator dominate enhancers and super enhancers and can explain genome-wide Mediator localization. We identify E-box transcription factor Tcf4 as a key regulator of NSCs. Tcf4 interacts with Mediator, colocalizes with Mediator at super enhancers and regulates neurogenic transcription factor genes with super enhancers and broad H3K4me3 domains. Our data suggest that high binding-affinity for Mediator is an important organizing feature in the transcriptional network that determines NSC identity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Enhancer Elements, Genetic / genetics
  • Gene Expression Regulation, Developmental / physiology*
  • Gene Regulatory Networks / physiology*
  • Histones / metabolism
  • Humans
  • Jumonji Domain-Containing Histone Demethylases / metabolism
  • Mediator Complex / metabolism*
  • Neural Stem Cells / physiology*
  • Neurogenesis / genetics*
  • Oxidoreductases, N-Demethylating / metabolism
  • Promoter Regions, Genetic / genetics
  • Protein Interaction Mapping
  • Protein Interaction Maps / genetics
  • Protein-Arginine N-Methyltransferases / metabolism
  • Transcription Factor 4 / metabolism*
  • Transcription, Genetic / physiology


  • Histones
  • Mediator Complex
  • TCF4 protein, human
  • Transcription Factor 4
  • histone H3 trimethyl Lys4
  • JMJD1C protein, human
  • Jumonji Domain-Containing Histone Demethylases
  • Oxidoreductases, N-Demethylating
  • Protein-Arginine N-Methyltransferases
  • coactivator-associated arginine methyltransferase 1