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Gene & Protein in Disease Pediatric glioma circadian clock genes

by impacting circadian rhythm generation or instead receptor subfamily 1 group D member 1, NR1D1 (Rev-
processes that are regulated by the clock output proteins erb-alpha); NR1D2 (Rev-erb-beta); period 1, PER1; PER2;
but are not necessarily dependent on circadian timing. PER3; RAR related orphan receptor A, RORA; RORB,
Unlike adult gliomas, the expression pattern of TIMELESS. In addition, ancillary genes were included
circadian clock-related genes has not been well examined whose proteins modulate the amplitude and stability of
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in pediatric gliomas. Here, we examined 19 datasets the rhythm : Basic helix-loop-helix family member e41,
quantifying pediatric and human glioma transcription BHLHE41 (DEC2) or are major components of the clock’s
to describe how genes that serve in the clock mechanism output pathway: D-box binding PAR bZIP transcription
and the circadian timing system are expressed. We relied factor, DBP; hepatic leukemia factor, PAR bZIP family
on internet data portals that provide statistical tools for member, HLF; and thyrotroph embryonic factor, PAR
comparing gene expression and access to multiple adult bZIP family member, TEF that are controlled by BMAL1
and CLOCK and nuclear factor, interleukin 3 regulated,
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and pediatric glioma datasets. Altered expression of NFIL3, controlled by Rev-erb-alpha. 35
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circadian clock genes has been characterized in adult GBM
tumor cells, and elevated expression of key components of The selected circadian set of 20 genes includes the 13
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the circadian clock in GBM, such as BMAL1, is recognized genes in the gene set KEGG_CIRCADIAN_RHYTHM_
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as an indicator of poor patient survival. Although GBM MAMMAL (https://www.gsea-msigdb.org/gsea/msigdb/
is less common among pediatric cancers, we were able human/geneset/KEGG_CIRCADIAN_RHYTHM_
to compare clock gene expression in adult and pediatric MAMMAL), except for the exclusion of two gene family
GBM and in pilocytic astrocytoma (PA) of adult and members (CSNK1D and BHLHE40). From these 20 genes,
pediatric patients, which is a low-grade tumor named for we also examined a subset of 12 core transcription factor
its morphologically distinct, hair-shaped cancer cells. PA is genes that serve influential and intimate roles in the
a common pediatric central nervous system tumor (ages 0 molecular mechanism of the circadian clock (ARNTL,
to 19 years) but is rare in adults. 12,30 Yet, it comprises about CLOCK, CRY1, CRY2, NR1D1, NR1D2, PER1, PER2, PER3,
1.5% of adult brain cancers. Furthermore, included in this RORA, RORB, and TIMELESS).
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analysis were medulloblastoma (MB) and ependymoma The Internet tools and sequence used to explore the
(EP) pediatric tumors that are both low-grade but can activity of circadian genes in pediatric and adult gliomas:
progress to more aggressive cancers and reappear later in (i) GlioVis to compare gene expression in normal brain
life. These common pediatric brain cancers differ between tissue with GBM and lower grade gliomas (LGG)
children and adults in their locations and molecular through microarray data derived from adult and
subtypes. In the present study, clock gene expression in pediatric patients
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four previously defined MB subtypes was examined, which (ii) TIMER2.0 to compare with Gliovis GBM microarray
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are also associated with different patient outcomes. results
Expression of the clock genes in original and recurrent (iii) UCSC Cell Viewer to compare clock gene expression
tumors in pediatric low-grade gliomas and GBM tumors in pediatric glioma subtypes and cell types previously
was also compared. identified through single-cell RNA sequencing
2. Methods (scRNA-seq)
(iv) Gliovis to compare the expression of the clock gene
2.1. Transcriptome data access and analysis set in four established subtypes of medulloblastoma,
Publicly available collections of pediatric and adult glioma which is the most common pediatric glioma
gene expression data were explored through the GlioVis (v) Gene Expression Omnibus (GEO) to evaluate
data portal for visualization and analysis of brain tumor pediatric glioma clock gene expression according to
expression datasets, http://gliovis.bioinfo.cnio.es/. The age
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database was accessed until November 30, 2024. The set (vi) Gliovis to compare recurrent with original tumor
of circadian genes we tested was compiled from various expression in datasets from ependymoma and
sources and includes genes that serve in the core circadian pediatric GBM.
clock mechanism. The set is listed here along with the To maximize chances of detecting significant
respective proteins wherever their names differ from the differences, selected datasets were restricted to ones with
genes: aryl hydrocarbon receptor nuclear translocator such at least five patient samples in each group analyzed. In the
as, ARNTL (BMAL1); ARNTL2; CLOCK; cryptochrome first step, each usable pediatric or adult dataset accessed
circadian regulator 1, CRY1; CRY2; casein kinase 1 epsilon, through GlioVis was examined to find differences in gene
CSNK1E; neuronal PAS domain protein 2, NPAS2; nuclear expression between the normal, non-tumor brain tissue,

Volume 4 Issue 2 (2025) 3 doi: 10.36922/gpd.4112