Systematic lncRNA mapping to genome-wide co-essential modules uncovers cancer dependency on uncharacterized lncRNAs
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Curated by eLife
Evaluation Summary:
Mitra et al. developed an analysis framework using large-scale pan-cancer omics datasets to discover the roles of 30 long non-coding RNAs (lncRNAs) in cancer proliferation and growth. Direct function-testing experiments were also performed to validate the biological mechanisms of two lncRNAs. The analysis framework developed here can serve as a resource to study the functions of lncRNA in cancer, and the computational framework can also be further extended to study cancer-relevant transcriptional and post-transcriptional regulation.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their name with the authors.)
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Abstract
Quantification of gene dependency across hundreds of cell lines using genome-scale CRISPR screens has 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 noncoding RNAs (lncRNAs), which are key regulators of many cellular processes, 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 10 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 p roliferation- s uppressive l nc R NAs ( 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.
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Author Response
Reviewer #1 (Public Review):
Mitra et al. extensively utilized the publicly available pan-cancer multi-omics datasets including CCLE, TCGA, RNAseq, and ChIPseq datasets from GEO, and conducted impressive computational analysis work to discover the potential regulatory functions of lncRNA at the pan-cancer level. The idea of using co-essential modules generated by Wainberg et al. 2021 is very interesting and was important to leverage the genome-wide set of functional modules to identify the new lncRNA functions. The overall statistical analyses are rigorous, and the evidence in this paper is logical and solid, especially given the additional RNAseq/ChIPseq data analysis. The validation experiments using cell lines were also appropriate. Overall, this is an excellent paper that combines both dry and wet lab experiments …
Author Response
Reviewer #1 (Public Review):
Mitra et al. extensively utilized the publicly available pan-cancer multi-omics datasets including CCLE, TCGA, RNAseq, and ChIPseq datasets from GEO, and conducted impressive computational analysis work to discover the potential regulatory functions of lncRNA at the pan-cancer level. The idea of using co-essential modules generated by Wainberg et al. 2021 is very interesting and was important to leverage the genome-wide set of functional modules to identify the new lncRNA functions. The overall statistical analyses are rigorous, and the evidence in this paper is logical and solid, especially given the additional RNAseq/ChIPseq data analysis. The validation experiments using cell lines were also appropriate. Overall, this is an excellent paper that combines both dry and wet lab experiments to systematically discover unknown functions of lncRNAs in cancer.
We thank the reviewer for recognizing our study as statistically rigorous, logical, and impressive and that has used multiple approaches and validation to systematically identify critical proliferation/growth regulatory functions of previously uncharacterized lncRNAs in cancer.
Reviewer #2 (Public Review):
Mitra and colleagues performed statistical analyses to evaluate associations between lncRNAs and mRNAs, using transcriptome data generated in tumor tissue samples in multiple cancer types from both CCLE and TCGA projects. They further integrated the association results into previously wellcharacterized co-essential pathways/modules (Wainberg et al., 2021), together with additional pathway/Hallmark genesets annotations, aiming to explore function potential for lncRNAs. Based on these analyses, they characterized 30 high-confidence pan-cancer proliferation/growth-regulating lncRNAs. Importantly, they provided in vitro functional evidence to verify potential tumor-suppressive roles of two prioritized lncRNAs (PSLR-1 and PSLR-2) in proliferation and growth in two lung adenocarcinoma cell models. Overall, this is a well-motivated and conducted study, especially given the large number of lncRNAs that currently have poor-characterized functions. The findings in this manuscript could advance the overall understanding of the roles of lncRNAs in cancer formation and progression.
We thank the Reviewer for recognizing the quality of our study and its importance in increasing the understanding of lncRNAs in cancer development and progression.
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Evaluation Summary:
Mitra et al. developed an analysis framework using large-scale pan-cancer omics datasets to discover the roles of 30 long non-coding RNAs (lncRNAs) in cancer proliferation and growth. Direct function-testing experiments were also performed to validate the biological mechanisms of two lncRNAs. The analysis framework developed here can serve as a resource to study the functions of lncRNA in cancer, and the computational framework can also be further extended to study cancer-relevant transcriptional and post-transcriptional regulation.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
Mitra et al. extensively utilized the publicly available pan-cancer multi-omics datasets including CCLE, TCGA, RNAseq, and ChIPseq datasets from GEO, and conducted impressive computational analysis work to discover the potential regulatory functions of lncRNA at the pan-cancer level. The idea of using co-essential modules generated by Wainberg et al. 2021 is very interesting and was important to leverage the genome-wide set of functional modules to identify the new lncRNA functions. The overall statistical analyses are rigorous, and the evidence in this paper is logical and solid, especially given the additional RNAseq/ChIPseq data analysis. The validation experiments using cell lines were also appropriate. Overall, this is an excellent paper that combines both dry and wet lab experiments to systematically …
Reviewer #1 (Public Review):
Mitra et al. extensively utilized the publicly available pan-cancer multi-omics datasets including CCLE, TCGA, RNAseq, and ChIPseq datasets from GEO, and conducted impressive computational analysis work to discover the potential regulatory functions of lncRNA at the pan-cancer level. The idea of using co-essential modules generated by Wainberg et al. 2021 is very interesting and was important to leverage the genome-wide set of functional modules to identify the new lncRNA functions. The overall statistical analyses are rigorous, and the evidence in this paper is logical and solid, especially given the additional RNAseq/ChIPseq data analysis. The validation experiments using cell lines were also appropriate. Overall, this is an excellent paper that combines both dry and wet lab experiments to systematically discover unknown functions of lncRNAs in cancer.
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Reviewer #2 (Public Review):
Mitra and colleagues performed statistical analyses to evaluate associations between lncRNAs and mRNAs, using transcriptome data generated in tumor tissue samples in multiple cancer types from both CCLE and TCGA projects. They further integrated the association results into previously well-characterized co-essential pathways/modules (Wainberg et al., 2021), together with additional pathway/Hallmark genesets annotations, aiming to explore function potential for lncRNAs. Based on these analyses, they characterized 30 high-confidence pan-cancer proliferation/growth-regulating lncRNAs. Importantly, they provided in vitro functional evidence to verify potential tumor-suppressive roles of two prioritized lncRNAs (PSLR-1 and PSLR-2) in proliferation and growth in two lung adenocarcinoma cell models. Overall, this …
Reviewer #2 (Public Review):
Mitra and colleagues performed statistical analyses to evaluate associations between lncRNAs and mRNAs, using transcriptome data generated in tumor tissue samples in multiple cancer types from both CCLE and TCGA projects. They further integrated the association results into previously well-characterized co-essential pathways/modules (Wainberg et al., 2021), together with additional pathway/Hallmark genesets annotations, aiming to explore function potential for lncRNAs. Based on these analyses, they characterized 30 high-confidence pan-cancer proliferation/growth-regulating lncRNAs. Importantly, they provided in vitro functional evidence to verify potential tumor-suppressive roles of two prioritized lncRNAs (PSLR-1 and PSLR-2) in proliferation and growth in two lung adenocarcinoma cell models. Overall, this is a well-motivated and conducted study, especially given the large number of lncRNAs that currently have poor-characterized functions. The findings in this manuscript could advance the overall understanding of the roles of lncRNAs in cancer formation and progression.
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