CHD2 Regulates Neuron-glioma Interactions in Pediatric Glioma.

in Cancer discovery by Xu Zhang, Shoufu Duan, Panagiota E Apostolou, Xiaoping Wu, Jun Watanabe, Matthew Gallitto, Tara Barron, Kathryn R Taylor, Pamelyn J Woo, Xu Hua, Hui Zhou, Hong-Jian Wei, Nicholas McQuillan, Kyung-Don Kang, Gregory K Friedman, Peter D Canoll, Kenneth Chang, Cheng-Chia Wu, Rintaro Hashizume, Christopher R Vakoc, Michelle Monje, Guy M McKhann, Joseph A Gogos, Zhiguo Zhang

TLDR

  • The study found that a protein called CHD2 helps control how brain cells called neurons interact with cancer cells called gliomas. The study showed that when CHD2 is removed from glioma cells, the cells become less able to survive and grow, and the interactions between neurons and gliomas are disrupted. The study also found that CHD2 works with another protein called FOSL1 to control which genes are turned on or off in glioma cells. The findings suggest that targeting CHD2 could be a new way to treat gliomas.

Abstract

High-grade gliomas (HGG) are deadly diseases for both adult and pediatric patients. Recently, it has been shown that neuronal activity promotes progression of multiple subgroups of HGG. However, epigenetic mechanisms that govern this process remain elusive. Here we report that the chromatin remodeler CHD2 regulates neuron-glioma interactions in diffuse midline glioma (DMG) characterized by onco-histone H3.1K27M. Depletion of CHD2 in H3.1K27M DMG cells compromises cell viability and neuron-to-glioma synaptic connections in vitro, neuron-induced proliferation of H3.1K27M DMG cells in vitro and in vivo, activity-dependent calcium transients in vivo, and extends the survival of H3.1K27M DMG-bearing mice. Mechanistically, CHD2 coordinates with the transcription factor FOSL1 to control the expression of axon-guidance and synaptic genes in H3.1K27M DMG cells. Together, our study reveals a mechanism whereby CHD2 controls the intrinsic gene program of the H3.1K27M DMG subtype, which in turn regulates the tumor growth-promoting interactions of glioma cells with neurons.

Overview

  • The study investigates the role of chromatin remodeler CHD2 in regulating neuron-glioma interactions in diffuse midline glioma (DMG) characterized by onco-histone H3.1K27M. The study aims to understand the epigenetic mechanisms that govern this process and its impact on tumor growth-promoting interactions of glioma cells with neurons. The hypothesis being tested is that depletion of CHD2 in H3.1K27M DMG cells will compromise cell viability, neuron-to-glioma synaptic connections, neuron-induced proliferation, activity-dependent calcium transients, and extend the survival of H3.1K27M DMG-bearing mice. The methodology used for the experiment includes depletion of CHD2 in H3.1K27M DMG cells, in vitro and in vivo assays to measure cell viability, neuron-to-glioma synaptic connections, neuron-induced proliferation, activity-dependent calcium transients, and survival of H3.1K27M DMG-bearing mice. The primary objective of the study is to reveal a mechanism whereby CHD2 controls the intrinsic gene program of the H3.1K27M DMG subtype, which in turn regulates the tumor growth-promoting interactions of glioma cells with neurons.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions or interventions, specifically the depletion of CHD2 in H3.1K27M DMG cells. The results show that depletion of CHD2 compromises cell viability, neuron-to-glioma synaptic connections, neuron-induced proliferation, activity-dependent calcium transients, and extends the survival of H3.1K27M DMG-bearing mice. These findings suggest that CHD2 plays a crucial role in regulating neuron-glioma interactions in H3.1K27M DMG and that its depletion can inhibit tumor growth-promoting interactions of glioma cells with neurons. The key findings of the study support the hypothesis that CHD2 controls the intrinsic gene program of the H3.1K27M DMG subtype, which in turn regulates the tumor growth-promoting interactions of glioma cells with neurons.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice. The identification of CHD2 as a key regulator of neuron-glioma interactions in H3.1K27M DMG provides insights into the epigenetic mechanisms that govern this process and its impact on tumor growth-promoting interactions of glioma cells with neurons. The study also highlights the potential of targeting CHD2 as a therapeutic strategy for H3.1K27M DMG. However, the study has limitations, such as the use of a specific subtype of HGG and the need for further validation of the findings in vivo. Future research directions could include investigating the role of CHD2 in other subtypes of HGG, exploring the molecular mechanisms underlying the interaction between CHD2 and FOSL1, and testing the efficacy of CHD2 inhibitors as a therapeutic strategy for H3.1K27M DMG.
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