Transcriptional stress induces the overexpression of novel lncRNAs that regulate the BRCA1 locus

Long non-coding RNAs (lncRNAs) have been shown to play a role during transcriptional regulation in response to stress. However, their function under stress caused by transcriptional inhibition has not yet been addressed. Using genome-wide assays to elucidate the transcriptional response in human cells caused by RNA polymerase II transcription inhibition, we found three novel regulatory lncRNAs, TILR-1, TILR-2, and LINC00910, that are upregulated as a response to this transcriptional stress. Knockdown experiments showed that the expression of these RNAs is interdependent, and together, they regulate transcription of the nearby BRCA1 locus. The lack of these novel regulatory transcripts also resulted in an increase in cellular proliferation and survival. Public transcriptomic data from different cell lines treated with a variety of transcriptional inhibitors or with heat shock and arsenic stress showed that TILR-1, TILR-2, and LINC00910 are commonly upregulated in a broad array of stress conditions. Evolutionary analysis showed that TILR-1, TILR-2, and LINC00910 are highly conserved among primates, and their emergence correlates with the duplication of the bidirectional promoter of BRCA1 and NBR1. We conclude that that coordinate transcription of TILR-1, TILR-2, and LINC00910 is stimulated generally by stress and the resulting lncRNAs are novel, functionally-conserved regulators of the BRCA1 locus.