Oncogenic lncRNA transgene transcription modulates epigenetic memory at a naïve chromosomal locus

Maintaining genome integrity is essential for the proper functioning and development of organisms. An intriguing aspect is that neocentromeres can form at non-centromeric sites. CENP-A, a key epigenetic marker of centromeres, is often mislocalized to ectopic sites in cancers when overexpressed. Its deposition on centromeres relies on transcription of centromeric non-coding RNAs. Subsequently, ectopic CENP-A is frequently found at transcriptionally active and chromosome breakpoint regions. We previously engineered a stable ectopic CENP-A site on a naïve chromosome by overexpressing PCAT2, a non-centromeric oncogenic lncRNA that recruits CENP-A to its transcribing locus. We tracked cells with this transgene to analyze the longevity of ectopic CENP-A. We discovered that this induced epigenetic memory was lost due to suppression by epigenetic silencing mechanisms, restoring CENP-A to previous levels. These findings suggest that cells have mechanisms to prevent neocentromere formation at ectopic sites by suppressing transcription unless selective pressure favors it.