Diffuse midline glioma (DMG) is a highly aggressive and fatal pediatric high-grade glioma that primarily affects critical regions of the central nervous system, such as the pons, thalamus, and spinal cord. Due to the high surgical risks and poor prognosis associated with DMG, treatment options for patients are extremely limited.

Conventional treatments, including surgery, radiotherapy, and chemotherapy, have shown limited efficacy, particularly with radiochemotherapy, which only temporarily controls tumor progression without significantly extending patient survival. Most patients succumb to the disease within two years of diagnosis, and effective therapeutic strategies are currently lacking.

One of the key pathological features of DMG is the lysine-to-methionine mutation at position 27 of histone H3 (H3K27M), which disrupts the epigenomic regulation of cells and drives rapid cancer progression. Studies have shown that epigenetic therapies can reprogram histone modifications in DMG tumor cells, thereby suppressing the expression of genes associated with tumor progression. However, the scarcity of DMG samples and the complexity of culturing tumor cells have hindered progress in both research and treatment.

In response, researchers have developed HiTIP-seq, a microarray-based high-throughput in situ tagged immunoprecipitation sequencing technology. Compared to traditional chromatin immunoprecipitation sequencing (ChIP-seq), HiTIP-seq enables high-throughput retrieval of high-quality epigenomic modification information from limited cell samples, providing new strategies for studying diseases like DMG that rely on scarce sample sources.

The study is published in the journal hLife.

The study demonstrates that the combination of epigenetic drugs Panobinostat and Tazemetostat can reprogram histone modifications in tumor cells, thereby suppressing the expression of genes associated with cancer progression. Using HiTIP-seq, the researchers conducted an in-depth analysis of epigenetic modifications in 3D cell cultures derived from DMG patients, revealing that these drugs effectively inhibit tumor cell growth by increasing H3K27 acetylation (H3K27ac) and decreasing H3K27 trimethylation (H3K27me3).

Furthermore, integrative transcriptomic analysis (RNA-seq) showed that the combination therapy activates the Wnt signaling pathway inhibitory factor 1 (WIF1), thereby inhibiting tumor cell proliferation and dissemination. This discovery not only highlights the potential sensitivity of DMG to epigenetic therapy but also provides critical scientific insights for future DMG treatment strategies.

In conclusion, the HiTIP-seq platform enables the acquisition of high-quality epigenomic modification information from limited sample sizes. Coupled with high-throughput microarray technology, this approach allows for simultaneous analysis of multiple samples and drug combinations.

This innovation paves the way for novel research and therapeutic strategies targeting diffuse midline glioma (DMG), offering new hope for patients. Moreover, HiTIP-seq provides a powerful tool for advancing epigenetic research in other cancers, driving significant progress in the field of cancer therapeutics.

More information: Zhongyao Chen et al, HiTIP-seq profiles epigenomic reprogramming of patient-derived diffuse midline glioma stem cells to epigenetic therapy, hLife (2024). DOI: 10.1016/j.hlife.2024.07.004

Provided byTsinghua University Press