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

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

Author information

1
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
2
Institute for Academic Medicine, The Methodist Hospital Research Institute, Houston, TX 77030, USA; Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, The Methodist Hospital Research Institute, Houston, TX 77030, USA; Weill Cornell Medical College, Cornell University, New York, NY 10065, USA.
3
Department of Pathology and Immunology, Department of Neuroscience, Program in Developmental Biology, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute of Texas Children's Hospital, Houston, TX 77030, USA.
4
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA.
5
Institute for Academic Medicine, The Methodist Hospital Research Institute, Houston, TX 77030, USA; Weill Cornell Medical College, Cornell University, New York, NY 10065, USA; Department of Neurosurgery, The Methodist Hospital Research Institute, Houston, TX 77030, USA.
6
Department of Pediatrics - Research, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
7
Department of Molecular Oncology and Cancer Biology and Evolution Program, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.
8
Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
9
Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.
10
Division of Biostatistics, Dan L. Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
11
Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL 60611, USA.
12
Institute for Academic Medicine, The Methodist Hospital Research Institute, Houston, TX 77030, USA; Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, The Methodist Hospital Research Institute, Houston, TX 77030, USA; Weill Cornell Medical College, Cornell University, New York, NY 10065, USA. Electronic address: kchen2@houstonmethodist.org.
13
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA. Electronic address: mglee@mdanderson.org.

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

PMID:
29861161
PMCID:
PMC6528658
DOI:
10.1016/j.molcel.2018.04.028
[Indexed for MEDLINE]
Free PMC Article

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