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Autonomous rhythmic activity in glioma networks drives brain tumor growth

ABSTRACT: Glioblastoma cell networks harbor a plastic population of highly active glioblastoma cells that display rhythmic Ca2+ oscillations and are particularly connected to others. Targeting the autonomous rhythmic activity of periodic tumor cells by pharmacological interference with the potassium channel KCa3.1 strongly compromised global network communication. This led to a marked reduction of tumor cell viability within the entire network, reduced tumor growth in mice, and prolonged animal survival. The dependency of glioblastoma networks on periodic Ca2+ activity generates a vulnerability that can be exploited for the development of novel therapies, with KCa3.1 inhibiting drugs as one example. To investigate the molecular mechanism of KCa3.1 blockade, we exposed glioblastoma cells to Senicapoc, a selective inhinitor of the KCa3.1 channel, and performed gene expression profiling analysis using data obtained from RNA-Seq.

ORGANISM(S): Homo sapiens

PROVIDER: GSE215365 | GEO | 2022/10/19

REPOSITORIES: GEO

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Project description:Purpose: Many mammalian genes exhibit circadian expression patterns concordant with periodic binding of transcription factors, chromatin modifications and chromosomal interactions. We determined whether lamina-associated domains (LADs) display oscillatory circadian patterns of interaction with nuclear lamin B1 during hte circadian cycle, and identified any relationship to changes in gene expression patterns in oscillatory LADs or in their vinicity. Methods: To this end, we mapped LADs by chromatin immunoprecipitation-sequencing (ChIP-seq) of lamin B1 (LMNB1) (antibody ab16048, Abcam) from mouse livers colected every 6 h, for 30 h, after entrainment of the circadian clock by 24-h fasting and refeeding. Gene expression profiles were also analyzed by RNA-sequencing (RNA-seq) at the same time points. Results and Conclusions: We report periodic interactions of chromatin domains with nuclear lamin B1, suggesting rhythmic associations of fractions of the genome with the nuclear lamina. Entrainment of the circadian clock by fasting and refeeding is accompanied in mouse liver by a gain of lamin-chromatin interactions followed by oscillations in these interactions at hundreds of lamina-associated domains (LADs). A subset of these oscillations exhibit periodicity and affect one or both LAD borders or entire stand-alone LADs. Periodic LADs are however not a dominant feature of these variable LADs, as most LADs are conserved during the circadian cycle. LAD oscillations are for the most part asynchronous between the 5’ and 3’ ends of LADs. Periodic LADs also uncoupled from gene expression patterns, periodic or not, within or in vicinity of these LADs. Accordingly, periodic genes, including central clock-control genes, are located megabases away from LADs, suggesting their residence in a transcriptionally permissive environment throughout the circadian cycle. Our data suggest autonomous oscillatory associations of fractions of the genome with the nuclear lamina, providing new evidence for rhythmic spatial configurations of chromatin. However, our data also argue that periodic LADs constitute a minor fraction of variable LADs, and reflect stochasticity in variable lamin-chromatin interactions during the circadian cycle.