Remodeling of the enhancer landscape during macrophage activation is coupled to enhancer transcription

Mol Cell. 2013 Aug 8;51(3):310-25. doi: 10.1016/j.molcel.2013.07.010.


Recent studies suggest a hierarchical model in which lineage-determining factors act in a collaborative manner to select and prime cell-specific enhancers, thereby enabling signal-dependent transcription factors to bind and function in a cell-type-specific manner. Consistent with this model, TLR4 signaling primarily regulates macrophage gene expression through a pre-existing enhancer landscape. However, TLR4 signaling also induces priming of ∼3,000 enhancer-like regions de novo, enabling visualization of intermediates in enhancer selection and activation. Unexpectedly, we find that enhancer transcription precedes local mono- and dimethylation of histone H3 lysine 4 (H3K4me1/2). H3K4 methylation at de novo enhancers is primarily dependent on the histone methyltransferases Mll1, Mll2/4, and Mll3 and is significantly reduced by inhibition of RNA polymerase II elongation. Collectively, these findings suggest an essential role of enhancer transcription in H3K4me1/2 deposition at de novo enhancers that is independent of potential functions of the resulting eRNA transcripts.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • CCAAT-Enhancer-Binding Proteins / metabolism
  • Cells, Cultured
  • DNA Methylation
  • Enhancer Elements, Genetic*
  • Gene Expression
  • Gene Expression Regulation
  • Histone-Lysine N-Methyltransferase / metabolism
  • Histones / genetics
  • Histones / metabolism
  • Macrophage Activation / genetics*
  • Macrophages / immunology
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Myeloid-Lymphoid Leukemia Protein / metabolism
  • NF-kappa B / metabolism
  • Proto-Oncogene Proteins / metabolism
  • RNA Polymerase II / antagonists & inhibitors
  • Sequence Analysis, DNA
  • Signal Transduction
  • Toll-Like Receptor 4 / metabolism*
  • Trans-Activators / metabolism
  • Transcription Factor RelA / metabolism
  • Transcription, Genetic


  • CCAAT-Enhancer-Binding Proteins
  • Histones
  • NF-kappa B
  • Proto-Oncogene Proteins
  • Rela protein, mouse
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Trans-Activators
  • Transcription Factor RelA
  • proto-oncogene protein Spi-1
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase
  • Kmt2a protein, mouse
  • Kmt2b protein, mouse
  • MLL3 protein, mouse
  • MLL4 protein, mouse
  • RNA Polymerase II

Associated data

  • GEO/GSE21512
  • GEO/GSE23622
  • GEO/GSE48759