OCAD University Open Research Repository

MLL5 Orchestrates a Cancer Self-Renewal State by Repressing the Histone Variant H3.3 and Globally Reorganizing Chromatin

Gallo, Marco and Coutinho, Fiona J. and Vanner, Robert J. and Gayden, Tenzin and Mack, Stephen C. and Murison, Alex and Remke, Marc and Li, Ren and Takayama, Naoya and Desai, Kinjal and Lee, Lilian and Lan, Xiaoyang and Park, Nicole I. and Barsyte-Lovejoy, Dalia and Smil, David and Sturm, Dominik and Kushida, Michelle M. and Head, Renee and Cusimano, Michael D. and Bernstein, Mark and Clarke, Ian D. and Dick, John E. and Pfister, Stefan M. and Rich, Jeremy N. and Arrowsmith, Cheryl H. and Taylor, Michael D. and Jabado, Nada and Bazett-Jones, David P. and Lupien, Mathieu and Dirks, Peter B. (2015) MLL5 Orchestrates a Cancer Self-Renewal State by Repressing the Histone Variant H3.3 and Globally Reorganizing Chromatin. Cancer Cell, 28 (6). pp. 715-729. ISSN 15356108

Full text not available from this repository.
Official URL: https://doi.org/10.1016/j.ccell.2015.10.005

Abstract

Mutations in the histone 3 variant H3.3 have been identified in one-third of pediatric glioblastomas (GBMs), but not in adult tumors. Here we show that H3.3 is a dynamic determinant of functional properties in adult GBM. H3.3 is repressed by mixed lineage leukemia 5 (MLL5) in self-renewing GBM cells. MLL5 is a global epigenetic repressor that orchestrates reorganization of chromatin structure by punctuating chromosomes with foci of compacted chromatin, favoring tumorigenic and self-renewing properties. Conversely, H3.3 antagonizes self-renewal and promotes differentiation. We exploited these epigenetic states to rationally identify two small molecules that effectively curb cancer stem cell properties in a preclinical model. Our work uncovers a role for MLL5 and H3.3 in maintaining self-renewal hierarchies in adult GBM.

Item Type: Article
Divisions: Faculty of Liberal Arts & Sciences
Date Deposited: 21 Mar 2018 14:34
Last Modified: 21 Mar 2018 14:34
URI: http://openresearch.ocadu.ca/id/eprint/2205

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