MLL4 Is Required to Maintain Broad H3K4me3 Peaks and Super-Enhancers at Tumor Suppressor Genes

Mol Cell. 2018 Jun 7;70(5):825-841.e6. doi: 10.1016/j.molcel.2018.04.028. Epub 2018 May 31.

Abstract

Super-enhancers are large clusters of enhancers that activate gene expression. Broad trimethyl histone H3 lysine 4 (H3K4me3) often defines active tumor suppressor genes. However, how these epigenomic signatures are regulated for tumor suppression is little understood. Here we show that brain-specific knockout of the H3K4 methyltransferase MLL4 (a COMPASS-like enzyme, also known as KMT2D) in mice spontaneously induces medulloblastoma. Mll4 loss upregulates oncogenic Ras and Notch pathways while downregulating neuronal gene expression programs. MLL4 enhances DNMT3A-catalyzed DNA methylation and SIRT1/BCL6-mediated H4K16 deacetylation, which antagonize expression of Ras activators and Notch pathway components, respectively. Notably, Mll4 loss downregulates tumor suppressor genes (e.g., Dnmt3a and Bcl6) by diminishing broad H3K4me3 and super-enhancers and also causes widespread impairment of these epigenomic signatures during medulloblastoma genesis. These findings suggest an anti-tumor role for super-enhancers and provide a unique tumor-suppressive mechanism in which MLL4 is necessary to maintain broad H3K4me3 and super-enhancers at tumor suppressor genes.

Keywords: DNA methylation; H4K16 deacetylation; MLL4; Notch; Ras; broad H3K4me3; epigenetics; histone methyltransferase; super-enhancers; tumor suppressor.

Publication types

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

MeSH terms

  • Acetylation
  • Animals
  • Cell Proliferation
  • Cerebellar Neoplasms / genetics*
  • Cerebellar Neoplasms / metabolism
  • Cerebellar Neoplasms / pathology
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • DNA Methylation*
  • Gene Expression Regulation, Neoplastic
  • Genes, Tumor Suppressor*
  • Genes, ras
  • Histone-Lysine N-Methyltransferase / deficiency
  • Histone-Lysine N-Methyltransferase / genetics*
  • Lysine
  • Medulloblastoma / genetics*
  • Medulloblastoma / metabolism
  • Medulloblastoma / pathology
  • Mice, Knockout
  • Oncogenes*
  • Protein Processing, Post-Translational*
  • Proto-Oncogene Proteins c-bcl-6 / genetics
  • Proto-Oncogene Proteins c-bcl-6 / metabolism
  • Receptors, Notch / genetics
  • Receptors, Notch / metabolism
  • Signal Transduction
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism

Substances

  • Bcl6 protein, mouse
  • Proto-Oncogene Proteins c-bcl-6
  • Receptors, Notch
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA methyltransferase 3A
  • Histone-Lysine N-Methyltransferase
  • MLL4 protein, mouse
  • Sirt1 protein, mouse
  • Sirtuin 1
  • Lysine