Hypoxia-inducible factor stabilisation-related lncRNAs in retinopathy of prematurity

Abstract

Long non-coding RNAs (lncRNAs) play an important role in the response to many diseases. The previous study reported the transcriptomes of mice that were cured of oxygen-induced retinopathy (OIR, retinopathy of prematurity (ROP) model) by hypoxia-inducible factor (HIF) stabilisation via HIF prolyl hydroxylase inhibition using the isoquinolone Roxadustat or the 2-oxoglutarateanalog dimethyloxalylglycine (DMOG). However, there is little understanding of how those genes are regulated. In the present study, 6918 known lncRNAs and 3654 novel lncRNAs were obtained, and a series of differentially expressed lncRNAs (DELncRNAs) were also identified. By cis- and trans-regulation analyses, the target genes of DELncRNAs were predicted. Functional analysis demonstrated that multiple genes were involved in the MAPK signalling pathway, adipocytokine signalling pathway was regulated by the DELncRNAs. By HIF-pathway analysis, two lncRNAs Gm12758 and Gm15283 were found that can regulate the HIF-pathway by targeting the Vegfa, Pgk1, Pfkl, Eno1, Eno1b and Aldoa genes. In conclusion, the present study provided a series of lncRNAs for further understanding and protecting the extremely premature infant from oxygen toxicity.

Impact Statement

• What is already known on this subject? Roxadustat can prevent oxygen-induced retinopathy (OIR) by two pathways: direct retinal hypoxia-inducible factor (HIF) stabilisation and induction of aerobic glycolysis or indirect hepatic HIF-1 stabilisation and increased serum angiokines. However, underlying the long non-coding RNAs (lncRNAs) that may regulate the HIF stabilisation-related genes have not been investigated thoroughly.

• What do the results of this study add? Six thousand nine hundred and eighteen known lncRNAs and 3654 novel lncRNAs were identified. GO and KEGG enrichment analysis showed that the MAPK signalling pathway and adipocytokine signalling pathway were regulated by the differentially expressed lncRNAs (DELncRNAs). Two lncRNAs Gm12758 and Gm15283 were found that may regulate the HIF-pathway by targeting the Vegfa, Pgk1, Pfkl, Eno1, Eno1b and Aldoa genes.

• What are the implications of these findings for clinical practice and/or further research? It provides a further rationale for protecting severe premature infants from oxygen poisoning.

Keywords:

• ncRNAs
• hypoxia-inducible factor
• Roxadustat
• DMOG
• target genes

Author contributions

DQC conceived and designed the experiments. MKD and ZHC contributed to paper writing. YMC and ZC contributed to the data analysis.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The data were downloaded from the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE74170; NCBI tracking system no. 17567121).

Additional information

Funding

This work was supported by Zhejiang Natural Science Youth Science Foundation [LQ19H040008], the Key Research and Development Plan of Zhejiang Provincial Department of Science and Technology [2018C03010] and the Natural Science Foundation of Zhejiang Province [LQ20H040003].