Molecular Cell
Volume 70, Issue 5, 7 June 2018, Pages 825-841.e6
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Article
MLL4 Is Required to Maintain Broad H3K4me3 Peaks and Super-Enhancers at Tumor Suppressor Genes

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Highlights

  • Brain-specific Mll4 loss in mice results in spontaneous medulloblastoma

  • MLL4 upregulates DNMT3A-catalyzed DNA methylation to repress Ras activators

  • MLL4 enhances SIRT1/BCL6-mediated H4K16 deacetylation to downregulate Notch pathways

  • MLL4 establishes broad H3K4me3 and super-enhancers to activate tumor suppressor genes

Summary

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

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

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