Temporal gene expression patterns in the coral Euphyllia paradivisa reveal the complexity of biological clocks in the cnidarian-algal symbiosis.

Studying chronobiology in reef-building corals is challenging due to the tightly coupled symbiosis with their photosynthetic algae, Symbiodiniaceae. Although symbiosis requires metabolic synchronization and coordination of cellular processes in the holobiont, the cross-talk between the host and symbiont's clocks is still puzzling. Here, we use the mesophotic coral Euphyllia paradivisa to examine temporal gene expression patterns in symbiotic and aposymbiotic morphs exposed to natural light/dark cycles and constant darkness. Our comparative transcriptomic analyses revealed circadian and circatidal cycles of gene expression with a predominant diel pattern in both coral morphs. We found a substantial number of transcripts consistently rhythmic under both light conditions, including genes likely involved in the cnidarians' circadian clock, thus indicating that an endogenous clock, which can oscillate independently from the Symbiodiniaceae clock, exists in E. paradivisa. The analysis further manifests the remarkable impacts of symbiosis on transcriptional rhythms and implies that the algae's presence influences the host's biorhythm.

miR-504 modulates the stemness and mesenchymal transition of glioma stem cells and their interaction with microglia via delivery by extracellular vesicles.

Glioblastoma (GBM) is a highly aggressive tumor with poor prognosis. A small subpopulation of glioma stem cells (GSCs) has been implicated in radiation resistance and tumor recurrence. In this study we analyzed the expression of miRNAs associated with the functions of GSCs using miRNA microarray analysis of these cells compared with human neural stem cells. These analyses identified gene clusters associated with glioma cell invasiveness, axonal guidance, and TGF-ß signaling. miR-504 was significantly downregulated in GSCs compared with NSCs, its expression was lower in GBM compared with normal brain specimens and further decreased in the mesenchymal glioma subtype. Overexpression of miR-504 in GSCs inhibited their self-renewal, migration and the expression of mesenchymal markers. The inhibitory effect of miR-504 was mediated by targeting Grb10 expression which acts as an oncogene in GSCs and GBM. Overexpression of exogenous miR-504 resulted also in its delivery to cocultured microglia by GSC-secreted extracellular vesicles (EVs) and in the abrogation of the GSC-induced polarization of microglia to M2 subtype. Finally, miR-504 overexpression prolonged the survival of mice harboring GSC-derived xenografts and decreased tumor growth. In summary, we identified miRNAs and potential target networks that play a role in the stemness and mesenchymal transition of GSCs and the miR-504/Grb10 pathway as an important regulator of this process. Overexpression of miR-504 exerted antitumor effects in GSCs as well as bystander effects on the polarization of microglia via delivery by EVs.