Transcriptomic Profiling and H3K27me3 Distribution Reveal Both Demethylase-Dependent and Independent Regulation of Developmental Gene Transcription in Cell Differentiation

PLoS One. 2015 Aug 11;10(8):e0135276. doi: 10.1371/journal.pone.0135276. eCollection 2015.


The removal of histone H3 trimethylation at lysine residue 27 (H3K27me3) plays a critical role in the transcriptional initiation of developmental genes. The H3K27me3-specific KDM6 demethylases JMJD3 and UTX are responsible for the transcriptional initiation of various developmental genes, but some genes are expressed in a KDM6 demethylase-independent manner. To address the role of H3K27me3 in the retinoic acid (RA)-induced differentiation of the human carcinoma NCCIT cell line, we inhibited JMJD3 and UTX using the H3K27me3 demethylase inhibitor GSK-J4. The commitment of JMJD3/UTX-inhibited cells to a specific fate was delayed, and transcriptome profiling also revealed the differential expression of genes related to cell fate specification in demethylase-inactivated cells; the expression levels of RA metabolism and HOX family genes significantly decreased. We observed a weak correlation between H3K27me3 enrichment and transcriptional repression in the control and JMJD/UTX-inhibited cells, except for a few sets of developmental genes that are indispensable for cell fate specification. Taken together, these results provide the H3K27me3 landscape of a differentiating cell line and suggest that both demethylase-dependent and demethylase-independent transcriptional regulation play a role in early differentiation and developmental gene expression activated by H3K27me3 demethylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzazepines / pharmacology
  • Cell Differentiation / drug effects
  • Cell Differentiation / genetics*
  • Cell Line, Tumor
  • DNA Methylation
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental* / drug effects
  • Gene Knockout Techniques
  • Histones / metabolism*
  • Humans
  • Jumonji Domain-Containing Histone Demethylases / genetics
  • Pyrimidines / pharmacology
  • Reproducibility of Results
  • Transcriptome*
  • Tretinoin / pharmacology


  • Benzazepines
  • GSK-J4
  • Histones
  • Pyrimidines
  • Tretinoin
  • Jumonji Domain-Containing Histone Demethylases
  • KDM6B protein, human

Grant support

This work was supported by by grant 2011-0030049 from the National Research Foundation of Korea ( funded by the Korean Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.