Roles of Chromatin Remodeler CHD2 in Diffuse Midline Glioma with Onco-Histone Mutations

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Diffuse midline gliomas (DMG)-H3K27 altered, which include diffuse intrinsic pontine gliomas (DIPG), represent the leading cause of glioma-related deaths in children and adolescents. Challenges in surgical resection, resistance to conventional chemotherapies contribute to the dismal prognosis. Therefore, it is imperative to elucidate the molecular basis of DIPG and to identify novel drug targets for this deadly disease. Somatic mutations at one of the 15 genes encoding histone H3, most frequently at either H3F3A or HIST1H3B gene, are found in 80% of DIPG tumors, replacing histone H3 lysine 27 with methionine (H3K27M). H3F3A and HIST1H3 encode histone H3 variant H3.3 and canonical H3.1, respectively. Of these “H3K27M tumors”, about 80% and 20% are H3.3K27M and H3.1K27M, respectively. Furthermore, H3.1K27M and H3.3K27M DIPG tumors show distinct gene expression signatures and are associated with distinct driver genetic mutations. Recently, it has been shown that DIPG cells interact with surrounding neurons, which promote the proliferation and invasion of DIPG cells. However, it is largely unknown how the unique gene expression pattern of H3.1K27M DIPG is regulated to promote tumorigenesis and the interactions between tumor cells and neurons. We hypothesize that chromatin regulators control the unique gene expression pattern and tumor-neuron interactions in H3.1K27M DIPG tumors. To test this hypothesis, we performed a CRISPR/Cas9 screen to identify chromatin regulators that when depleted specifically reduce the fitness of H3.1K27M, but not H3.3K27M DIPG cells. Through this effort, we discovered CHD2, a member of the CHD family chromatin remodelers. CHD2 is known for its role in gene regulation and nucleosome assembly of H3.3, and its dysregulation is linked to cancer and neurological syndromes. However, its roles in H3.1K27M DIPG were unexpected. We found that CHD2 depletion reduces the expression of genes involved in axon guidance and neurogenesis in H3.1K27M, but not H3.3K27M DIPG cells. Furthermore, CHD2 depletion in H3.1K27M cells resulted in increased H3K27me3 and reduced H3K27 acetylation (H3K27ac). Based on these exciting results, we propose to elucidate molecular mechanisms underlying the unique dependence of H3,1K27M DIPG cells on CHD2, and test the hypotheses that CHD2 regulates the expression of genes in these cells for their interaction with neurons. Furthermore, we will test the hypothesis that inhibition of CHD2 and its regulated events (H3K27ac, H3K27me3 and genes involved in axon guidance) compromises tumor growth using patient derived xenograft (PDX) mouse models. Together, the proposed studies will provide both conceptual advances in the regulation of the unique gene expression signatures in H3.1K27M DIPG and the regulation of the tumor-neuron interactions, an emerging field of cancer neuroscience. Further, the proposed studies will also provide in vivo data to support future development of novel targeted therapies for this incurable malignancy.