MLL4 Is Required to Maintain Broad H3K4me3 Peaks and Super-Enhancers at Tumor Suppressor Genes. Academic Article uri icon

Overview

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.

publication date

  • May 31, 2018

Research

keywords

  • Cerebellar Neoplasms
  • DNA Methylation
  • Genes, Tumor Suppressor
  • Histone-Lysine N-Methyltransferase
  • Medulloblastoma
  • Oncogenes
  • Protein Processing, Post-Translational

Identity

PubMed Central ID

  • PMC6528658

Scopus Document Identifier

  • 85047217455

Digital Object Identifier (DOI)

  • 10.1016/j.molcel.2018.04.028

PubMed ID

  • 29861161

Additional Document Info

volume

  • 70

issue

  • 5