Metformin Treatment Modulates Long Non-Coding RNA Isoforms Expression in Human Cells

Abstract

Long noncoding RNAs (lncRNAs) undergo splicing and have multiple transcribed isoforms. Nevertheless, for lncRNAs, as well as for mRNA, measurements of expression are routinely performed only at the gene level. Metformin is the first-line oral therapy for type 2 diabetes mellitus and other metabolic diseases. However, its mechanism of action remains not thoroughly explained. Transcriptomic analyses using metformin in different cell types reveal that only protein-coding genes are considered. We aimed to characterize lncRNA isoforms that were differentially affected by metformin treatment on multiple human cell types (three cancer, two non-cancer) and to provide insights into the lncRNA regulation by this drug. We selected six series to perform a differential expression (DE) isoform analysis. We also inferred the biological roles for lncRNA DE isoforms using in silico tools. We found the same isoform of an lncRNA (AC016831.6-205) highly expressed in all six metformin series, which has a second exon putatively coding for a peptide with relevance to the drug action. Moreover, the other two lncRNA isoforms (ZBED5-AS1-207 and AC125807.2-201) may also behave as cis-regulatory elements to the expression of transcripts in their vicinity. Our results strongly reinforce the importance of considering DE isoforms of lncRNA for understanding metformin mechanisms at the molecular level.

The anti-diabetic effects of metformin are mediated by regulating long non-coding RNA

“…How metformin acts on lncRNAs is not clear; a bioinformatics study showed that metformin promotes different expressions of lncRNA isoforms among lung cells, kidney cells, embryonic cells, hepatocytes, and pancreatic cells. For example, NEAT1-202, the canonical isoform of the NEAT1 gene, is upregulated in five out of six cell lines by metformin treatment, but other isoforms showed different fold change directions ( Conceicao et al, 2022 ). This may explain different results for the same lncRNA in different studies.…”