Alu RNA modulates the expression of cell cycle genes in human fibroblasts

Alu retroelements, whose retrotransposition requires prior transcription by RNA polymerase III to generate Alu RNAs, represent the most numerous non-coding RNA (ncRNA) gene family in the human genome. Alu transcription is generally kept to extremely low levels by tight epigenetic silencing, but it has been reported to increase under different types of cell perturbation, such as viral infection and cancer. Alu RNAs, being able to act as gene expression regulators, might be directly involved in the mechanisms determining cellular behavior in such perturbed states. To directly address the regulatory potential of Alu RNAs, we generated IMR90 fibroblast and HeLa cell lines stably overexpressing two slightly different Alu RNAs, and analyzed genome-wide the expression changes of protein-coding genes through RNA-Sequencing. Among the genes that were upregulated or downregulated in response to Alu overexpression in IMR90, but not in HeLa cells, we found a highly significant enrichment of pathways involved in cell cycle progression and mitotic entry, including increased expression of the key cell cycle transcriptional regulator FOXM1 and several FOXM1-regulated genes. Overall, the results of our analysis suggest that increased Alu RNA favors cell cycle progression thus contributing to enable sustained cell proliferation which is an important factor of cancer development and progression. Overall design: mRNA profiles of human fibroblasts (IMR90) and HeLa cells that overexpress the Alu retrotransposons AluSq2 and AluSx. The experiments were performed in duplicate using Illumina HiSeq4000