Effect of depletion of sin-lncRNA in senescent IMR90 fibroblasts
Despite the classical view of senescence as passive growth arrest, it is an active process with profound implications for cellular homeostasis. Indeed, senescent cells remain metabolically active to be able to cope with the energetic demand of the senescence program, although the precise mechanisms underlying this metabolic reprogramming are just beginning to emerge. Here we have identified sin-lncRNA, a previously uncharacterized lncRNA, highly specific of senescent cells, and transcriptionally induced by the master regulator of senescence C/EBPß. While being strongly activated in senescence, sin-lncRNA knockdown reinforces the senescence program by altering oxidative phosphorylation and impairing mitochondrial function. Sin-lncRNA interacts with the TCA enzyme dihydrolipoamide S-succinyltransferase (DLST) to facilitate its proper function. sin-lncRNA depletion increases DLST nuclear translocation, favoring a metabolic shift from oxidative phosphorylation to a glycolytic phenotype. Moreover, while sin-lncRNA expression remains low in highly proliferative cancer cells, it is strongly induced upon cisplatin-induced senescence. Knockdown of sin-lncRNA in ovarian cancer cells results in deficient oxygen consumption and increased extracellular acidification, sensitizing the cells to cisplatin treatment. Altogether, these results indicate that sin-lncRNA is specifically induced in cellular senescence to maintain metabolic homeostasis. Our findings reveal a new regulatory mechanism in which lncRNA contributes to the adaptive metabolic changes in senescent cells, unveiling the existence of an RNA-dependent metabolic network specific to senescent cells. Overall design: To investigate the function of sin-lncRNA in senescence we depleted sin-lncRNA using siRNAs in 4OHT treated IMR90 for 3 days.  Poly-A selected RNAseq from control or sin-lncRNA knockdown IMR90 senescent cells in triplicates.