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

Research output: Contribution to journalArticle

17 Citations (Scopus)

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)
JournalMolecular Cell
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Tumor Suppressor Genes
Medulloblastoma
Epigenomics
Down-Regulation
Gene Expression
Neoplasms
Methyltransferases
DNA Methylation
Oncogenes
Histones
Lysine
Up-Regulation
Brain
Enzymes

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

MLL4 Is Required to Maintain Broad H3K4me3 Peaks and Super-Enhancers at Tumor Suppressor Genes. / Dhar, Shilpa S.; Zhao, Dongyu; Lin, Tao; Gu, Bingnan; Pal, Khusboo; Wu, Sarah J.; Alam, Hunain; Lv, Jie; Yun, Kyuson; Gopalakrishnan, Vidya; Flores, Elsa R.; Northcott, Paul A.; Rajaram, Veena; Li, Wei; Shilatifard, Ali; Sillitoe, Roy V.; Chen, Kaifu; Lee, Min Gyu.

In: Molecular Cell, 01.01.2018.

Research output: Contribution to journalArticle

Dhar, SS, Zhao, D, Lin, T, Gu, B, Pal, K, Wu, SJ, Alam, H, Lv, J, Yun, K, Gopalakrishnan, V, Flores, ER, Northcott, PA, Rajaram, V, Li, W, Shilatifard, A, Sillitoe, RV, Chen, K & Lee, MG 2018, 'MLL4 Is Required to Maintain Broad H3K4me3 Peaks and Super-Enhancers at Tumor Suppressor Genes', Molecular Cell. https://doi.org/10.1016/j.molcel.2018.04.028
Dhar, Shilpa S. ; Zhao, Dongyu ; Lin, Tao ; Gu, Bingnan ; Pal, Khusboo ; Wu, Sarah J. ; Alam, Hunain ; Lv, Jie ; Yun, Kyuson ; Gopalakrishnan, Vidya ; Flores, Elsa R. ; Northcott, Paul A. ; Rajaram, Veena ; Li, Wei ; Shilatifard, Ali ; Sillitoe, Roy V. ; Chen, Kaifu ; Lee, Min Gyu. / MLL4 Is Required to Maintain Broad H3K4me3 Peaks and Super-Enhancers at Tumor Suppressor Genes. In: Molecular Cell. 2018.
@article{9b7d813d1f644f4ba382ba1bae4f99a0,
title = "MLL4 Is Required to Maintain Broad H3K4me3 Peaks and Super-Enhancers at Tumor Suppressor Genes",
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.",
keywords = "broad H3K4me3, DNA methylation, epigenetics, H4K16 deacetylation, histone methyltransferase, MLL4, Notch, Ras, super-enhancers, tumor suppressor",
author = "Dhar, {Shilpa S.} and Dongyu Zhao and Tao Lin and Bingnan Gu and Khusboo Pal and Wu, {Sarah J.} and Hunain Alam and Jie Lv and Kyuson Yun and Vidya Gopalakrishnan and Flores, {Elsa R.} and Northcott, {Paul A.} and Veena Rajaram and Wei Li and Ali Shilatifard and Sillitoe, {Roy V.} and Kaifu Chen and Lee, {Min Gyu}",
year = "2018",
month = "1",
day = "1",
doi = "10.1016/j.molcel.2018.04.028",
language = "English (US)",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",

}

TY - JOUR

T1 - MLL4 Is Required to Maintain Broad H3K4me3 Peaks and Super-Enhancers at Tumor Suppressor Genes

AU - Dhar, Shilpa S.

AU - Zhao, Dongyu

AU - Lin, Tao

AU - Gu, Bingnan

AU - Pal, Khusboo

AU - Wu, Sarah J.

AU - Alam, Hunain

AU - Lv, Jie

AU - Yun, Kyuson

AU - Gopalakrishnan, Vidya

AU - Flores, Elsa R.

AU - Northcott, Paul A.

AU - Rajaram, Veena

AU - Li, Wei

AU - Shilatifard, Ali

AU - Sillitoe, Roy V.

AU - Chen, Kaifu

AU - Lee, Min Gyu

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

KW - broad H3K4me3

KW - DNA methylation

KW - epigenetics

KW - H4K16 deacetylation

KW - histone methyltransferase

KW - MLL4

KW - Notch

KW - Ras

KW - super-enhancers

KW - tumor suppressor

UR - http://www.scopus.com/inward/record.url?scp=85047217455&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85047217455&partnerID=8YFLogxK

U2 - 10.1016/j.molcel.2018.04.028

DO - 10.1016/j.molcel.2018.04.028

M3 - Article

JO - Molecular Cell

JF - Molecular Cell

SN - 1097-2765

ER -