A UTX-MLL4-p300 Transcriptional Regulatory Network Coordinately Shapes Active Enhancer Landscapes for Eliciting Transcription

Mol Cell. 2017 Jul 20;67(2):308-321.e6. doi: 10.1016/j.molcel.2017.06.028.


Enhancer activation is a critical step for gene activation. Here we report an epigenetic crosstalk at enhancers between the UTX (H3K27 demethylase)-MLL4 (H3K4 methyltransferase) complex and the histone acetyltransferase p300. We demonstrate that UTX, in a demethylase activity-independent manner, facilitates conversion of inactive enhancers in embryonic stem cells to an active (H3K4me1+/H3K27ac+) state by recruiting and coupling the enzymatic functions of MLL4 and p300. Loss of UTX leads to attenuated enhancer activity, characterized by reduced levels of H3K4me1 and H3K27ac as well as impaired transcription. The UTX-MLL4 complex enhances p300-dependent H3K27 acetylation through UTX-dependent stimulation of p300 recruitment, while MLL4-mediated H3K4 monomethylation, reciprocally, requires p300 function. Importantly, MLL4-generated H3K4me1 further enhances p300-dependent transcription. This work reveals a previously unrecognized cooperativity among enhancer-associated chromatin modulators, including a unique function for UTX, in establishing an "active enhancer landscape" and defines a detailed mechanism for the joint deposition of H3K4me1 and H3K27ac.

Keywords: MLL4/KMT2D; UTX/HDM6A; active enhancer landscape; chromatin modification; enhancer regulation; epigenetic crosstalk; histone acetyltransferase; histone methyltransferase; p300/EP300; transcriptional activation.

MeSH terms

  • Animals
  • Chromatin / genetics
  • Chromatin / metabolism*
  • Chromatin Assembly and Disassembly
  • E1A-Associated p300 Protein / genetics
  • E1A-Associated p300 Protein / metabolism*
  • Embryonic Stem Cells / enzymology*
  • Enhancer Elements, Genetic*
  • Feedback, Physiological
  • Gene Regulatory Networks
  • HEK293 Cells
  • Histone Demethylases / genetics
  • Histone Demethylases / metabolism*
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Histones / metabolism
  • Humans
  • Male
  • Methylation
  • Mice
  • RNA Interference
  • Transcription, Genetic*
  • Transcriptional Activation*
  • Transfection


  • Chromatin
  • Histones
  • Histone Demethylases
  • Utx protein, mouse
  • Histone-Lysine N-Methyltransferase
  • MLL4 protein, mouse
  • E1A-Associated p300 Protein
  • Ep300 protein, mouse