Retinoic Acid Induces Ubiquitination-Resistant RIP140/LSD1 Complex to Fine-Tune Pax6 Gene in Neuronal Differentiation

Stem Cells. 2016 Jan;34(1):114-23. doi: 10.1002/stem.2190. Epub 2015 Oct 9.


Receptor-interacting protein 140 (RIP140) is a wide-spectrum coregulator for hormonal regulation of gene expression, but its activity in development/stem cell differentiation is unknown. Here, we identify RIP140 as an immediate retinoic acid (RA)-induced dual-function chaperone for LSD1 (lysine-specific demethylase 1). RIP140 protects LSD1's catalytic domain and antagonizes its Jade-2-mediated ubiquitination and degradation. In RA-induced neuronal differentiation, the increased RIP140/LSD1 complex is recruited by RA-elevated Pit-1 to specifically reduce H3K4me2 modification on the Pax6 promoter, thereby repressing RA-induction of Pax6. This study reveals a new RA-induced gene repressive mechanism that modulates the abundance, enzyme quality, and recruitment of histone modifier LSD1 to neuronal regulator Pax6, which provides a homeostatic control for RA induction of neuronal differentiation.

Keywords: Embryonic stem cells; Neural differentiation; RIP140; Retinoic acid; Transcription factors.

MeSH terms

  • Animals
  • Cell Differentiation / drug effects
  • Gene Silencing / drug effects
  • Histone Demethylases / metabolism*
  • Immunoprecipitation
  • Mice
  • Microtubule-Associated Proteins / metabolism
  • Nuclear Receptor Co-Repressor 1 / metabolism*
  • PAX6 Transcription Factor / genetics*
  • PAX6 Transcription Factor / metabolism
  • Protein Binding / drug effects
  • Tretinoin / pharmacology*
  • Ubiquitination / drug effects*


  • Microtubule-Associated Proteins
  • Mtap2 protein, mouse
  • Nuclear Receptor Co-Repressor 1
  • PAX6 Transcription Factor
  • Tretinoin
  • Histone Demethylases
  • KDM1a protein, mouse