Nuclear microRNA-466c regulates Vegfa expression in response to hypoxia

PLoS One. 2022 Mar 31;17(3):e0265948. doi: 10.1371/journal.pone.0265948. eCollection 2022.

Abstract

MicroRNAs are well characterized in their role in silencing gene expression by targeting 3´-UTR of mRNAs in cytoplasm. However, recent studies have shown that miRNAs have a role in the regulation of genes in the nucleus, where they are abundantly located. We show here that in mouse endothelial cell line (C166), nuclear microRNA miR-466c participates in the regulation of vascular endothelial growth factor a (Vegfa) gene expression in hypoxia. Upregulation of Vegfa expression in response to hypoxia was significantly compromised after removal of miR-466c with CRISPR-Cas9 genomic deletion. We identified a promoter-associated long non-coding RNA on mouse Vegfa promoter and show that miR-466c directly binds to this transcript to modulate Vegfa expression. Collectively, these observations suggest that miR-466c regulates Vegfa gene transcription in the nucleus by targeting the promoter, and expands on our understanding of the role of miRNAs well beyond their canonical role.

MeSH terms

  • Animals
  • Hypoxia / genetics
  • Mice
  • MicroRNAs* / genetics
  • RNA, Long Noncoding* / genetics
  • RNA, Messenger
  • Vascular Endothelial Growth Factor A* / metabolism

Substances

  • MicroRNAs
  • Mirn466 microRNA, mouse
  • RNA, Long Noncoding
  • RNA, Messenger
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse

Grants and funding

This work was funded by RNatives Oy (PL, TT, MPT), Academy of Finland Center of Excellence (SYH), Academy of Finland project funding #268376 (MPT), The Finnish Foundation for Cardiovascular Research (MPT), Eye and Tissue Bank Foundation (PL), Instrumentarium Science Foundation (PL) and ERC Advanced Grant CleverGenes (SYH). The funder [RNatives Oy] provided support in the form of salaries for authors [PL, TAT, MPT] and research materials, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.