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

Shilpa S. Dhar, Dongyu Zhao, Tao Lin, Bingnan Gu, Khusboo Pal, Sarah J. Wu, Hunain Alam, Jie Lv, Kyuson Yun, Vidya Gopalakrishnan, Elsa R. Flores, Paul A. Northcott, Veena Rajaram, Wei Li, Ali Shilatifard, Roy V. Sillitoe, Kaifu Chen*, Min Gyu Lee

*Corresponding author for this work

Research output: Contribution to journalArticle

26 Scopus citations

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. Dhar et al. show that MLL4 suppresses medulloblastoma by establishing super-enhancers and broad H3K4me3 to activate multiple mechanisms that lead to activation of tumor suppressor genes and repression of oncogenes.

Original languageEnglish (US)
Pages (from-to)825-841.e6
JournalMolecular cell
Volume70
Issue number5
DOIs
StatePublished - Jun 7 2018

    Fingerprint

Keywords

  • DNA methylation
  • H4K16 deacetylation
  • MLL4
  • Notch
  • Ras
  • broad H3K4me3
  • epigenetics
  • histone methyltransferase
  • super-enhancers
  • tumor suppressor

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Dhar, S. S., Zhao, D., Lin, T., Gu, B., Pal, K., Wu, S. J., Alam, H., Lv, J., Yun, K., Gopalakrishnan, V., Flores, E. R., Northcott, P. A., Rajaram, V., Li, W., Shilatifard, A., Sillitoe, R. V., Chen, K., & Lee, M. G. (2018). MLL4 Is Required to Maintain Broad H3K4me3 Peaks and Super-Enhancers at Tumor Suppressor Genes. Molecular cell, 70(5), 825-841.e6. https://doi.org/10.1016/j.molcel.2018.04.028