RT Journal Article
SR Electronic
T1 Systematic lncRNA mapping to genome-wide co-essential pathways uncovers cancer dependency on uncharacterized lncRNAs
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.02.03.478941
DO 10.1101/2022.02.03.478941
A1 Mitra, Ramkrishna
A1 Adams, Clare M.
A1 Eischen, Christine M.
YR 2022
UL http://biorxiv.org/content/early/2022/02/04/2022.02.03.478941.abstract
AB Quantification of gene dependency across hundreds of cell lines using genome-scale CRISPR screens have revealed co-essential pathways/modules and critical functions of uncharacterized genes. In contrast to protein-coding genes, robust CRISPR-based loss-of-function screens are lacking for long non-coding RNAs (lncRNAs), which are key regulators of many cellular process, leaving many essential lncRNAs unidentified and uninvestigated. Integrating copy- number, epigenetic, and transcriptomic data of >800 cancer cell lines with CRISPR-derived co-essential pathways, our method recapitulates known essential lncRNAs and predicts proliferation/growth dependency of 289 poorly characterized lncRNAs. Analyzing lncRNA dependencies across ten cancer types and their expression alteration by diverse growth- inhibitors across cell types, we prioritize 30 high-confidence pan-cancer proliferation/growth- regulating lncRNAs. Further evaluating two previously uncharacterized top proliferation-suppressive lncRNAs (PSLR-1, PSLR-2) showed they are transcriptionally regulated by p53, induced by multiple cancer treatments, and significantly correlate to increased cancer patient survival. These lncRNAs modulate G2 cell cycle-regulating genes within the FOXM1 transcriptional network, inducing a G2 arrest and inhibiting proliferation and colony formation. Collectively, our results serve as a powerful resource for exploring lncRNA-mediated regulation of cellular fitness in cancer, circumventing current limitations in lncRNA research.Competing Interest StatementDr. Eischen discloses research funding from AbbVie unrelated to this manuscript. The other authors declare no competing interests.