Investigating the Intracellular Compartmental Dynamics of miRNAs in Response to Hypoxia

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Abstract MicroRNAs (miRNAs) are a class of small non-coding RNAs (ncRNAs) with established functions in cytoplasmic gene regulation, where they interact with mRNA transcripts, impeding their translation—a process known as post-transcriptional gene silencing (PTGS). Recent studies have found that miRNAs and other components involved in PTGS are abundantly present in the nucleus of the cells, where they also play important roles in gene regulation. However, the understanding of their function in the nucleus is not well characterized, particularly in response to cellular stress. We conducted nuclear-cytoplasmic fractionation of primary human endothelial cells (ECs) to assess the distribution of miRNAs during hypoxia. The onset of hypoxia led to changes in miRNA expression in both nuclear and cytoplasmic compartments. Notably, a larger proportion of deregulated miRNAs were identified in the nucleus than in the cytoplasm upon hypoxia exposure. We focused on these nuclear-enriched, differentially expressed miRNAs to investigate their cellular functions and their effects on target mRNAs in different compartments. The data indicated a more pronounced alteration in nuclear mRNA expression compared to cytoplasmic expression, pointing towards a nuclear-specific role for these miRNAs. Several miRNAs influenced target mRNAs associated with pathways of cell proliferation and inflammation. Functional assays under hypoxia showed that miR-5091 and miR-7974 reduced EC cell proliferation, while miR-1246 increased it. Additionally, miR-3662 was found to regulate the secretion levels of specific cytokines, impacting the inflammatory response. Overall, our findings highlight the significant role of miRNAs in the nuclear compartment of ECs in modulating the hypoxic response and provide insights into their multifaceted functions.

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