RAR/RXR Binding Dynamics Distinguish Pluripotency From Differentiation Associated Cis-Regulatory Elements

Nucleic Acids Res. 2015 May 26;43(10):4833-54. doi: 10.1093/nar/gkv370. Epub 2015 Apr 20.

Abstract

In mouse embryonic cells, ligand-activated retinoic acid receptors (RARs) play a key role in inhibiting pluripotency-maintaining genes and activating some major actors of cell differentiation. To investigate the mechanism underlying this dual regulation, we performed joint RAR/RXR ChIP-seq and mRNA-seq time series during the first 48 h of the RA-induced Primitive Endoderm (PrE) differentiation process in F9 embryonal carcinoma (EC) cells. We show here that this dual regulation is associated with RAR/RXR genomic redistribution during the differentiation process. In-depth analysis of RAR/RXR binding sites occupancy dynamics and composition show that in undifferentiated cells, RAR/RXR interact with genomic regions characterized by binding of pluripotency-associated factors and high prevalence of the non-canonical DR0-containing RA response element. By contrast, in differentiated cells, RAR/RXR bound regions are enriched in functional Sox17 binding sites and are characterized with a higher frequency of the canonical DR5 motif. Our data offer an unprecedentedly detailed view on the action of RA in triggering pluripotent cell differentiation and demonstrate that RAR/RXR action is mediated via two different sets of regulatory regions tightly associated with cell differentiation status.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Cell Differentiation / genetics*
  • Embryonal Carcinoma Stem Cells
  • Gene Expression Regulation*
  • Genome
  • Mice
  • Nucleotide Motifs
  • Pluripotent Stem Cells / metabolism*
  • Receptors, Retinoic Acid / metabolism*
  • Response Elements*
  • Retinoid X Receptors / metabolism*
  • Transcription Factors / metabolism
  • Transcription, Genetic*
  • Tretinoin / pharmacology

Substances

  • Receptors, Retinoic Acid
  • Retinoid X Receptors
  • Transcription Factors
  • Tretinoin

Associated data

  • GEO/GSE56893