posted on 2024-09-04, 07:40authored byXu 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
CHD2 binds to the gene regulatory elements of axon-guidance and synaptic genes.
Funding
National Institute of Neurological Disorders and Stroke (NINDS)
United States Department of Health and Human Services
High-grade gliomas (HGG) are deadly diseases for both adult and pediatric patients. Recently, it has been shown that neuronal activity promotes the progression of multiple subgroups of HGG. However, epigenetic mechanisms that govern this process remain elusive. Here we report that the chromatin remodeler chromodomain helicase DNA-binding protein 2 (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.Significance: Neurons drive the proliferation and invasion of glioma cells. Here we show that chromatin remodeler chromodomain helicase DNA-binding protein 2 controls the epigenome and expression of axon-guidance and synaptic genes, thereby promoting neuron-induced proliferation of H3.1K27M diffuse midline glioma and the pathogenesis of this deadly disease.