Differences in the expression of genes used in circadian rhythm generation in adult and pediatric gliomas

Abstract

Altered circadian rhythms occur in several types of cancer cells. Expression of PER2, a core component of the circadian oscillator mechanism, and the related PER3 gene is suppressed in adult glioblastoma (GBM). GBM cell survival depends on the activity of the core clock gene ARNTL that expresses BMAL1 protein, and pharmacological manipulations of BMAL1 activity are promising novel anticancer treatments. Because circadian clock gene activity in pediatric gliomas is poorly understood relative to adult GBM, we completed a meta-analysis using 19 public transcriptome datasets to evaluate expression of core clock genes and selected clock-controlled genes in adult and pediatric GBM as well as medulloblastoma (MB), pilocytic astrocytoma (PA), and ependymoma (EP) tumors. Unlike adult GBM, PER2, and PER3 were not significantly downregulated in pediatric gliomas relative to non-tumor tissue. Adult GBM tissue displayed elevated expression of core clock gene CRY1 and clock-controlled gene NFIL3, unlike the pediatric GBM and low-grade gliomas. The TIMELESS clock gene was upregulated in all glioma types except PA. The clock gene set was differentially expressed across the four standard MB subtypes in pediatric datasets and was elevated in bulk-tumor measurements and single-cell RNA sequencing results from the Group 3 and 4 subtypes. Relative to older patients, MB samples from patients under 10 years of age had six repressed core clock genes. This study found that several types of malignant pediatric brain tumors have predictable expression patterns of specific circadian clock genes and may respond to treatments using pharmacological treatments exploiting these features.

Keywords

Circadian rhythm / Glioma stem cell / Glioblastoma / Medulloblastoma / Ependymoma / Pilocytic astrocytoma / Transcriptomics

Funding

Support for this project was provided internally by Bowling Green State University through assistance with computer technology.

Conflict of interest

The authors declare that they have no competing interests.

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