Retinoids induce stem cell differentiation via epigenetic changes

Semin Cell Dev Biol. 2013 Dec;24(10-12):701-5. doi: 10.1016/j.semcdb.2013.08.002. Epub 2013 Aug 21.


Vitamin A (all-trans retinol) and its active metabolites, collectively called retinoids, exert potent effects on stem cell differentiation and thus, the formation of the entire organism, in part via the modulation of the epigenome. All-trans retinoic acid (RA), through binding to the retinoic acid receptors (RARs), alters interactions of the RARs with various protein components of the transcription complex at numerous genes in stem cells, and some of these protein components of the transcription complex then either place or remove epigenetic marks on histones or on DNA, altering chromatin structure and leading to an exit from the self-renewing, pluripotent stem cell state. Different epigenetic mechanisms, i.e. first, primarily H3K27me3 marks and then DNA methylation, may be employed by embryonic stem cells and other stem cells for control of early vs. late stages of cell differentiation. Creating these stable epigenetic changes requires the actions of many molecules, including tet1, polycomb protein complexes (PRCs), miRNAs, DNA methyltransferases (DNMTs), and telomerase reverse transcriptase. A more complete understanding of retinoid-dependent stem cell differentiation should reward us with new insights into the failure to maintain a differentiated state that is an essential part of neoplastic cell transformation and cancer.

Keywords: 5-hydroxymethylcytosine; 5-methylcytosine; 5hmC; 5mC; CARM; DNA methylation; DNA methyltransferase; DNMT; Differentiation; ES; Histone methylation; MLL; PRC; Polycomb group-repressive complex; Polycomb/PRC; RA; RAR; RARE; Retinoic acid; Review; all-trans retinoic acid; co-activator associated arginine methyltransferase 1; embryonic stem; miRNA; micro RNA; mixed lineage leukemia; retinoic acid DNA response element; retinoic acid receptor.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Cell Differentiation / genetics*
  • DNA Methylation / genetics
  • Epigenesis, Genetic*
  • Humans
  • Polycomb-Group Proteins / metabolism
  • Retinoids / metabolism*
  • Stem Cells / cytology*
  • Stem Cells / metabolism


  • Polycomb-Group Proteins
  • Retinoids