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Publication

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

Molecular cell | 2018

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.

Pubmed ID: 29861161 RIS Download

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Associated grants

Agency: NINDS NIH HHS, United States
Id: R03 NS077021
Agency: NCI NIH HHS, United States
Id: R01 CA193466
Agency: NCI NIH HHS, United States
Id: P30 CA016672
Agency: NCI NIH HHS, United States
Id: R01 CA207109
Agency: NHLBI NIH HHS, United States
Id: R01 HL133254
Agency: NCI NIH HHS, United States
Id: R35 CA197569
Agency: NICHD NIH HHS, United States
Id: U54 HD083092
Agency: NCI NIH HHS, United States
Id: R01 CA157919
Agency: NCI NIH HHS, United States
Id: R01 CA207098
Agency: NINDS NIH HHS, United States
Id: R01 NS089664
Agency: NHGRI NIH HHS, United States
Id: R01 HG007538
Agency: NCI NIH HHS, United States
Id: R35 CA197452
Agency: NINDS NIH HHS, United States
Id: R01 NS079715

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