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 journalArticlepeer-review

113 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

Funding

We are thankful to Dr. M. McArthur for histopathological analysis, to S. Zhang and Dr. Z. Han for technical assistance, and to K. Michel, K. Maldonado, and C. Kingsley in the Small Animal Imaging Facility (supported by the NIH/NCI under core grant award P30CA16672) at the University of Texas MD Anderson Cancer Center for technical advice. We also thank the IDDRC neuropathology core (core grant award U54HD083092) and RNA In Situ Hybridization core at the Baylor College of Medicine for histology and image scan services. This work was supported in part by grants to M.G.L. from the Cancer Prevention and Research Institute of Texas (CPRIT) (RP140271), the NIH (R01CA157919, R01CA207098, and R01CA207109), and the Center for Cancer Epigenetics at the MD Anderson Cancer Center; by a grant to A.S. from the NIH (R35CA197569); by grants to W.L. from the CPRIT (RP150292) and the NIH (R01HG007538 and R01CA193466); by grants to V.G. from the CPRIT (RP150301) and the NIH (R01NS079715 and R03NS077021); by a grant to R.V.S. from the NIH (R01NS089664); by a grant to E.R.F. from the NIH (R35CA197452); and by a fellowship to S.S.D. from the Center for Cancer Epigenetics at the MD Anderson Cancer Center. K.C. was supported by startup funds from the Methodist Hospital Research Institute and by a grant from the NIH (R01HL133254). We are thankful to Dr. M. McArthur for histopathological analysis, to S. Zhang and Dr. Z. Han for technical assistance, and to K. Michel, K. Maldonado, and C. Kingsley in the Small Animal Imaging Facility (supported by the NIH/NCI under core grant award P30CA16672 ) at the University of Texas MD Anderson Cancer Center for technical advice. We also thank the IDDRC neuropathology core (core grant award U54HD083092 ) and RNA In Situ Hybridization core at the Baylor College of Medicine for histology and image scan services. This work was supported in part by grants to M.G.L. from the Cancer Prevention and Research Institute of Texas (CPRIT) ( RP140271 ), the NIH ( R01CA157919 , R01CA207098 , and R01CA207109 ), and the Center for Cancer Epigenetics at the MD Anderson Cancer Center ; by a grant to A.S. from the NIH ( R35CA197569 ); by grants to W.L. from the CPRIT ( RP150292 ) and the NIH ( R01HG007538 and R01CA193466 ); by grants to V.G. from the CPRIT ( RP150301 ) and the NIH ( R01NS079715 and R03NS077021 ); by a grant to R.V.S. from the NIH ( R01NS089664 ); by a grant to E.R.F. from the NIH ( R35CA197452 ); and by a fellowship to S.S.D. from the Center for Cancer Epigenetics at the MD Anderson Cancer Center . K.C. was supported by startup funds from the Methodist Hospital Research Institute and by a grant from the NIH ( R01HL133254 ).

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

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