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SMARCA4/Brg1 coordinates genetic and epigenetic networks underlying Shh-type medulloblastoma development

Oncogene volume 35, pages 5746–5758 (2016)Cite this article

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Abstract

Recent large-scale genomic studies have classified medulloblastoma into four subtypes: Wnt, Shh, Group 3 and Group 4. Each is characterized by specific mutations and distinct epigenetic states. Previously, we showed that a chromatin regulator SMARCA4/Brg1 is required for Gli-mediated transcription activation in Sonic hedgehog (Shh) signaling. We report here that Brg1 controls a transcriptional program that specifically regulates Shh-type medulloblastoma growth. Using a mouse model of Shh-type medulloblastoma, we deleted Brg1 in precancerous progenitors and primary or transplanted tumors. Brg1 deletion significantly inhibited tumor formation and progression. Genome-wide expression analyses and binding experiments indicate that Brg1 specifically coordinates with key transcription factors including Gli1, Atoh1 and REST to regulate the expression of both oncogenes and tumor suppressors that are required for medulloblastoma identity and proliferation. Shh-type medulloblastoma displays distinct H3K27me3 properties. We demonstrate that Brg1 modulates activities of H3K27me3 modifiers to regulate the expression of medulloblastoma genes. Brg1-regulated pathways are conserved in human Shh-type medulloblastoma, and Brg1 is important for the growth of a human medulloblastoma cell line. Thus, Brg1 coordinates a genetic and epigenetic network that regulates the transcriptional program underlying the Shh-type medulloblastoma development.

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Acknowledgements

We thank Drs Brent Orr (St. Jude Hospital), Wenzhe Niu and Zilai Zhang, and Mou Cao for technical support and Dr Chao Xing and the University of Texas Southwestern Sequencing Facility for performing the next-generation sequencing and RNA-seq analyses. We thank Drs Lin Gan and Jane Johnson for providing the Atoh1-Cre mice and Dr Ching-Ping Chang for providing human Brg1 shRNA constructs. This work was supported by grants from March of Dimes Foundation (JW), American Cancer Society (JW), NIMH (JW) and Department of Defense Visionary postdoc fellowship (XS).

Author contributions

JW and XS designed the experiments. XS, QW and JW performed the experiments and collected the data. XS and JW analyzed the results. JG and ZX performed the main bioinformatics analyses. JW wrote the manuscript with help from all the authors.

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  1. Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    X Shi, Q Wang & J I Wu

  2. Department of Biological Sciences, Center for Systems Biology, University of Texas at Dallas, Richardson, TX, USA

    J Gu & Z Xuan

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  1. X Shi
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Correspondence to J I Wu.

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Shi, X., Wang, Q., Gu, J. et al. SMARCA4/Brg1 coordinates genetic and epigenetic networks underlying Shh-type medulloblastoma development. Oncogene 35, 5746–5758 (2016). https://doi.org/10.1038/onc.2016.108

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