Coordinated regulation of Rel expression by MAP3K4, CBP, and HDAC6 controls phenotypic switching

Commun Biol. 2020 Aug 28;3(1):475. doi: 10.1038/s42003-020-01200-z.

Abstract

Coordinated gene expression is required for phenotypic switching between epithelial and mesenchymal phenotypes during normal development and in disease states. Trophoblast stem (TS) cells undergo epithelial-mesenchymal transition (EMT) during implantation and placentation. Mechanisms coordinating gene expression during these processes are poorly understood. We have previously demonstrated that MAP3K4-regulated chromatin modifiers CBP and HDAC6 each regulate thousands of genes during EMT in TS cells. Here we show that CBP and HDAC6 coordinate expression of only 183 genes predicted to be critical regulators of phenotypic switching. The highest-ranking co-regulated gene is the NF-κB family member Rel. Although NF-κB is primarily regulated post-transcriptionally, CBP and HDAC6 control Rel transcript levels by binding Rel regulatory regions and controlling histone acetylation. REL re-expression in mesenchymal-like TS cells induces a mesenchymal-epithelial transition. Importantly, REL forms a feedback loop, blocking HDAC6 expression and nuclear localization. Together, our work defines a developmental program coordinating phenotypic switching.

Publication types

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

MeSH terms

  • Animals
  • Epithelial Cells / metabolism
  • Epithelial-Mesenchymal Transition / genetics
  • Female
  • Gene Expression Regulation*
  • Histone Deacetylase 6 / metabolism*
  • Humans
  • MAP Kinase Kinase Kinase 4 / metabolism*
  • Male
  • Mice
  • Models, Biological
  • Oncogene Proteins v-rel / genetics*
  • Peptide Fragments / metabolism*
  • Phenotype*
  • Protein Transport
  • Proto-Oncogene Proteins c-met / metabolism
  • Sialoglycoproteins / metabolism*
  • Stem Cells / metabolism
  • Transcription Factors

Substances

  • Oncogene Proteins v-rel
  • Peptide Fragments
  • Sialoglycoproteins
  • Transcription Factors
  • bone sialoprotein (35-62), human
  • MET protein, human
  • Proto-Oncogene Proteins c-met
  • MAP Kinase Kinase Kinase 4
  • MAP3K4 protein, human
  • HDAC6 protein, human
  • Histone Deacetylase 6