Transcription factor-dependent 'anti-repressive' mammalian enhancers exclude H3K27me3 from extended genomic domains

Genes Dev. 2017 Dec 1;31(23-24):2391-2404. doi: 10.1101/gad.308536.117. Epub 2018 Jan 10.


Compacted chromatin and nucleosomes are known barriers to gene expression; the nature and relative importance of other transcriptional constraints remain unclear, especially at distant enhancers. Polycomb repressor complex 2 (PRC2) places the histone mark H3K27me3 predominantly at promoters, where its silencing activity is well documented. In adult tissues, enhancers lack H3K27me3, and it is unknown whether intergenic H3K27me3 deposits affect nearby genes. In primary intestinal villus cells, we identified hundreds of tissue-restricted enhancers that require the transcription factor (TF) CDX2 to prevent the incursion of H3K27me3 from adjoining areas of elevated basal marking into large well-demarcated genome domains. Similarly, GATA1-dependent enhancers exclude H3K27me3 from extended regions in erythroid blood cells. Excess intergenic H3K27me3 in both TF-deficient tissues is associated with extreme mRNA deficits, which are significantly rescued in intestinal cells lacking PRC2. Explaining these observations, enhancers show TF-dependent binding of the H3K27 demethylase KDM6A. Thus, in diverse cell types, certain genome regions far from promoters accumulate H3K27me3, and optimal gene expression depends on enhancers clearing this repressive mark. These findings reveal new "anti-repressive" function for hundreds of tissue-specific enhancers.

Keywords: CDX2; H3K27me3; KDM6A; PRC2; enhancers.

Publication types

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

MeSH terms

  • Animals
  • CDX2 Transcription Factor / genetics
  • Enhancer Elements, Genetic / physiology*
  • Erythroid Cells / metabolism
  • Female
  • Gene Expression Regulation*
  • Genome / genetics*
  • Histone Demethylases / metabolism
  • Histones / metabolism*
  • Intestine, Small / cytology
  • Intestine, Small / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Polycomb Repressive Complex 2 / genetics
  • Polycomb Repressive Complex 2 / metabolism
  • Protein Binding
  • Transcription Factors / metabolism*


  • CDX2 Transcription Factor
  • Cdx2 protein, mouse
  • Eed protein, mouse
  • Histones
  • Transcription Factors
  • Histone Demethylases
  • Utx protein, mouse
  • Polycomb Repressive Complex 2