Characterization of Long noncoding rnas in cellular senescence

Abstract

Senescence is a condition of permanent growth arrest that occurs when cells experience different potentially oncogenic insults and activate redundant tumor suppressor pathways to avoid tumor transformation. While the implication of numerous protein factors in the profound senescence-associated gene expression change is now well established, only recently the involvement of long noncoding RNAs (lncRNAs) in this process is emerging. In the last years, these non-coding transcripts have demonstrated to play crucial roles in multiple physiological and pathological processes by regulating virtually every level of gene expression. In the search of novel lncRNAs implicated in the senescent program, we isolated noncoding transcripts differentially associated in proliferating or senescent cells to the SWI/SNF complexes, chromatin remodelers that take part in the widespread epigenetic reorganization characterizing senescence progression. Among them, we identified and functionally characterized LINC00565, an oncogenic lncRNA specifically interacting with the SWI/SNF complexes in proliferating conditions to promote cell growth and survival in normal and tumor cells. We found that LINC00565 is transcribed from an enhancer region and epigenetically controls the activation of its neighbor pro-survival gene GAS6 and possibly other targets through its binding to the SWI/SNF complexes. Moreover, we evaluated the expression profile of human fibroblasts during senescence induction and identified a robust set of lncRNAs significantly induced in senescence. Among them, we focused on a cytoplasmic lncRNA, renamed senescence-induced lncRNA (sin-lncRNA), a novel senescence-specific lncRNA, strongly induced in senescent cells thanks to the direct transcriptional activation of the senescence master regulator C/EBPβ. We found that sin-lncRNA expression is boosted during late phases of senescence progression to negatively regulate this process, thus mitigating an over-activation of the senescent program and preventing an excessive inflammatory response.