Abstract
Non-coding RNAs (ncRNAs) play major roles in proper chromatin organization and function. Senescence, a strong anti-proliferative process and a major anticancer barrier, is associated with dramatic chromatin reorganization in heterochromatin foci. Here we analyze strand-specific transcriptome changes during oncogene-induced human senescence. Strikingly, while differentially expressed RNAs are mostly repressed during senescence, ncRNAs belonging to the recently described vlincRNA (very long intergenic ncRNA) class are mainly activated. We show that VAD, a novel antisense vlincRNA strongly induced during senescence, is required for the maintenance of senescence features. VAD modulates chromatin structure in cis and activates gene expression in trans at the INK4 locus, which encodes cell cycle inhibitors important for senescence-associated cell proliferation arrest. Importantly, VAD inhibits the incorporation of the repressive histone variant H2A.Z at INK4 gene promoters in senescent cells. Our data underline the importance of vlincRNAs as sensors of cellular environment changes and as mediators of the correct transcriptional response.
Highlights
Non-coding RNAs play major roles in proper chromatin organization and function
Non-coding RNAs are some of the major components required for proper chromatin function11. ncRNAs can be transcribed from known genes or from intergenic loci
We provide the first analysis of strand-specific transcriptome changes in senescent versus proliferative cells, independent of gene annotation and at a high resolution, in particular allowing the characterization of unannotated ncRNAs such as novel antisense transcripts
Summary
We tested whether VAD controls the expression of these neighbouring genes (DDAH1, CYR61, SYDE2 or ZNHIT6) None of these mRNAs were consistently affected by VAD depletion (Supplementary Fig. 12), indicating that the repression of these genes occurring during senescence is mediated, at least in part, through VAD-independent mechanisms. In senescent cells transfected by VAD siRNAs, H4ac and H3K4me[3] marks increased on all the regions where they would normally decrease in senescence (SYDE2 promoter, DDAH1 promoters, CYR61 promoter and coding region and the region between DDAH1 and CYR61 divergent promoters; Fig. 4d), while remaining unchanged on the ZNHIT6 or VAD promoters Taken together, these data indicate that VAD expression is important for setting up the chromatin landscape around its locus in senescent cells by removing activating chromatin marks on repressed promoters. Given that VAD is able to affect chromatin features, we concentrated on chromatin marks
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