Among the signals that control the epigenetic landscape, non-coding (nc)RNAs have been identified to play a major role but the generalization and the mechanisms of their activity are still poorly apprehended. Recent data using high-throughput technologies have profoundly changed our view on how the genomes are organized. Indeed transcriptome analyses have shown that large genomic regions are pervasively transcribed producing a broad variety of ncRNA which functions on the epigenome remain to be deciphered. Our recent works show that S. cerevisiae’s genome also supports production of non-coding protein large transcripts, which are strongly controlled by RNA decay pathways. Of specific interest are the lncRNA XUT that we described recently, mostly antisense to class II genes and associated with a consistent regulatory potential through epigenetic modifications. Interestingly, histone methyl transferase and histone deacetylase show strong interplays with large antisense ncRNA. Mechanistic insights of their regulatory activities will be presented and generalization of their function will be discussed, especially in human cells undergoing genetic instability.