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Elucidation of the BMI1 interactome identifies novel regulatory roles in glioblastoma

ABSTRACT: Glioblastoma (GBM) is the most common and aggressive intrinsic brain tumour in adults. Epigenetic mechanisms controlling normal brain development are often dysregulated in GBM. Among these, BMI1, a structural component of the Polycomb Repressive Complex 1 (PRC1), which promotes the H2AK119ub catalytic activity of Ring1B, is upregulated in GBM and its tumorigenic role has been shown in vitro and in vivo. Here, we have used protein and chromatin immunoprecipitation followed by mass spectrometry (MS) analysis to elucidate the protein composition of PRC1 in GBM and CRISPR/dCAS9-mediated modulation of BMI1 to assess its influence on protein interactions. We show that while well-established BMI1 functions such as control of cell proliferation and cell adhesion are PRC1-dependent, novel regulatory functions in mRNA splicing and cholesterol transport are PRC1 independent and may represent novel targetable mechanisms in GBM.

ORGANISM(S): Homo sapiens

PROVIDER: GSE159747 | GEO | 2021/03/04

REPOSITORIES: GEO

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Project description:NguyenLK2011 - Ubiquitination dynamics in Ring1B-Bmi1 system This theoretical model investigates the dynamics of Ring1B/Bmi1 ubiquitination to identify bistable switch-like and oscillatory behaviour in the system. Michaelis-Menten (MM) equations are used to formulate the model. However, the authors show that the dynamics persist even for Mass-Action kinetics. This SBML file is the MM version of the model. This model is described in the article: Switches, excitable responses and oscillations in the Ring1B/Bmi1 ubiquitination system. Nguyen LK, Muñoz-García J, Maccario H, Ciechanover A, Kolch W, Kholodenko BN. PLoS Comput. Biol. 2011 Dec; 7(12): e1002317 Abstract: In an active, self-ubiquitinated state, the Ring1B ligase monoubiquitinates histone H2A playing a critical role in Polycomb-mediated gene silencing. Following ubiquitination by external ligases, Ring1B is targeted for proteosomal degradation. Using biochemical data and computational modeling, we show that the Ring1B ligase can exhibit abrupt switches, overshoot transitions and self-perpetuating oscillations between its distinct ubiquitination and activity states. These different Ring1B states display canonical or multiply branched, atypical polyubiquitin chains and involve association with the Polycomb-group protein Bmi1. Bistable switches and oscillations may lead to all-or-none histone H2A monoubiquitination rates and result in discrete periods of gene (in)activity. Switches, overshoots and oscillations in Ring1B catalytic activity and proteosomal degradation are controlled by the abundances of Bmi1 and Ring1B, and the activities and abundances of external ligases and deubiquitinases, such as E6-AP and USP7. This model is hosted on BioModels Database and identified by: BIOMD0000000622. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Elucidation of the BMI1 interactome identifies novel regulatory roles in glioblastoma

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