Deletion of Mediator 1 suppresses TGFβ signaling leading to changes in epidermal lineages and regeneration

PLoS One. 2020 Aug 28;15(8):e0238076. doi: 10.1371/journal.pone.0238076. eCollection 2020.


Epidermal lineages and injury induced regeneration are controlled by transcriptional programs coordinating cellular signaling and epigenetic regulators, but the mechanism remains unclear. Previous studies showed that conditional deletion of the transcriptional coactivator Mediator 1 (Med1) changes epidermal lineages and accelerates wound re-epithelialization. Here, we studied a molecular mechanism by which Med1 facilitates these processes, in particular, by focusing on TGFβ signaling through genome wide transcriptome analysis. The expression of the TGF ligands (Tgfβ1/β2) and their downstream target genes is decreased in both normal and wounded Med1 null skin. Med1 silencing in cultured keratinocytes likewise reduces the expression of the ligands (TGFβ1/β2) and diminishes activity of TGFβ signaling as shown by decreased p-Smad2/3. Silencing Med1 increases keratinocyte proliferation and migration in vitro. Epigenetic studies using chromatin immuno-precipitation and next generation DNA sequencing reveals that Med1 regulates transcription of TGFβ components by forming large clusters of enhancers called super-enhancers at the regulatory regions of the TGFβ ligand and SMAD3 genes. These results demonstrate that Med1 is required for the maintenance of the TGFβ signaling pathway. Finally, we show that pharmacological inhibition of TGFβ signaling enhances epidermal lineages and accelerates wound re-epithelialization in skin similar to that seen in the Med1 null mice, providing new insights into epidermal regeneration.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Lineage
  • Cell Movement
  • Cell Proliferation
  • Down-Regulation
  • Epidermis / physiology
  • Keratinocytes / cytology
  • Keratinocytes / metabolism
  • Mediator Complex Subunit 1 / antagonists & inhibitors
  • Mediator Complex Subunit 1 / genetics*
  • Mediator Complex Subunit 1 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Regeneration / physiology*
  • Signal Transduction*
  • Skin / metabolism
  • Skin / pathology
  • Smad3 Protein / genetics
  • Smad3 Protein / metabolism
  • Transforming Growth Factor beta1 / genetics
  • Transforming Growth Factor beta1 / metabolism*
  • Transforming Growth Factor beta2 / genetics
  • Transforming Growth Factor beta2 / metabolism*
  • Up-Regulation


  • Med1 protein, mouse
  • Mediator Complex Subunit 1
  • RNA, Small Interfering
  • Smad3 Protein
  • Transforming Growth Factor beta1
  • Transforming Growth Factor beta2