Alternative transcribed 3' isoform of long non-coding RNA Malat1 inhibits mouse retinal oxidative stress

Summary: The function of the cancer-associated lncRNA Malat1 during aging is as-of-yet uncharacterized. Here, we show that Malat1 interacts with Nucleophosmin (NPM) in young mouse brain, and with Lamin A/C, hnRNP C, and KAP1 with age. RNA-seq and RT-qPCR reveal a persistent expression of Malat1_2 (the 3’isoform of Malat1) in Malat1Δ1 (5’-1.5 kb deletion) mouse retinas and brains at 1/4th level of the full-length Malat1, while Malat1_1 (the 5’isoform) in Malat1Δ2 (deletion of 3’-conserved 5.7 kb) at a much lower level, suggesting an internal promoter driving the 3’ isoform. The 1774 and 496 differentially expressed genes in Malat1Δ2 and Malat1Δ1 brains, respectively, suggest the 3’ isoform regulates gene expression in trans and the 5’ isoform in cis. Consistently, Malat1Δ2 mice show increased age-dependent retinal oxidative stress and corneal opacity, while Malat1Δ1 mice show no obvious phenotype. Collectively, this study reveals a physiological function of the lncRNA Malat1 3’-isoform during the aging process.