Control of gene expression in senescence through transcriptional read-through of convergent protein-coding genes [ChIP-Seq]

Antisense RNAs are non-coding RNAs, which can regulate their corresponding sense RNAs and are generally produced from specific promoters. By genome-wide approaches and in depth analyses at specific loci in human cells undergoing senescence, we uncover a family of antisense RNAs produced by transcriptional read-through at convergent protein-coding genes. Importantly, these antisense RNAs, that we named STARTs, repress the expression of their corresponding sense RNAs. We found that the elongation rate of RNA pol II is limited downstream of the TTS at START loci in proliferative cells. This allows transcription termination to occur before the RNA pol II reaches the convergent genes, thus preventing antisense RNA production and interference with the expression of the convergent genes. In proliferative cells, STARTs are repressed by the histone variant H2A.Z, whose local occupancy decreases in senescence. Our results thus uncover a novel mechanism of gene expression regulation, relying on the control of the expression of read-through antisense transcripts at convergent genes and underline the functional importance of the epigenetic control of RNA pol II elongation rate at intergenic regions.