Multi-hallmark long noncoding RNA maps reveal non-small cell lung cancer vulnerabilities

Esposito, Roberta; Polidori, Taisia; Meise, Dominik F.; Pulido-Quetglas, Carlos; Chouvardas, Panagiotis; Förster, Stefan; Schaerer, Paulina; Kobel, Andrea; Schlatter, Juliette; Kerkhof, Erik; Roemmele, Michaela; Rice, Emily; Zhu, Lina; Lanzós, Andrés; Guillén-Ramírez, Hugo A.; Basile, Giulia; Carrozzo, Irene; Vancura, Adrienne; Ullrich, Sebastian; Andrades, Álvaro; Harvey, Dylan; Medina, Pedro P.; Patrick, C.; Haefliger, Simon; Wang, Xin; Martínez, Iván; Ochsenbein, Adrian F.; Riether, Carsten; Johnson, Rory

doi:10.1016/j.xgen.2022.100171

Cited by 15 publications

(11 citation statements)

References 117 publications

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“…Indication of alternative TSSs for MALAT1 gene that substitute the targeted promoter in NSCLC cell lines studied. Regulation of proliferation, apoptosis, migration and invasion via the miR-374b-5p/SRSF7 and hsa-miR-200a/ZEB-1 axis in NSCLC [ 56 , 57 ]; Undetectable in A549 and H460 cells [ 58 ] DANCR Downregulated only in A549 cells and undetectable hsa-miR-214-5p levels in NSCLC cell lines; hypomethylated CpG island 93 at the 5′ end of the DANCR gene in both A549 and H460 NSCLC cells ( Fig. 2 E), indicating of additional regulatory transcriptional mechanisms for this lncRNA in NSCLC.…”

Section: Resultsmentioning

confidence: 99%

“…2 C–D), suggesting an exceptional role of ZBTB7A expression signature in the large cell lung carcinoma. Another important result was also the significant upregulation of hsa-miR-148b-3p only in H460 cell line, which is predicted to target ZBTB7A -mRNA ( Table 2 ) among other gene targets, and it is sponged by the H19 - and PVT1 -lncRNAs [ 58 , 62 ]; these traits render hsa-miR-148b-3p an attractive candidate regarding the differential regulation of ZBTB7A expression in lung large cell carcinoma. Its capability of attacking also DNMTs with other members of the miR-148/-152 family makes this molecule an essential epigenetic regulator and a novel potential target for lung cancer treatment [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

“Crosstalk between non-coding RNAs and transcription factor LRF in non-small cell lung cancer”

Spella,

Bochalis,

Athanasopoulou

et al. 2024

Non-coding RNA Research

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“Crosstalk between non-coding RNAs and transcription factor LRF in non-small cell lung cancer”

Spella,

Bochalis,

Athanasopoulou

et al. 2024

Non-coding RNA Research

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“…Pooled screening approaches using CRISPR-based technology have offered the possibility to evaluate mammalian gene function, including lncRNAs at genome scale levels Liu et al (2017) . More recently, they have been applied to cancer cell lines and have confirmed the oncogenic or tumor suppressor roles of some lncRNAs Esposito et al (2022) . This strategy is able to test a large number of candidates simultaneously but require well identified phenotypes such as cell proliferation, cell viability, or cell migration.…”

Section: Introductionmentioning

confidence: 99%

Detecting subtle transcriptomic perturbations induced by lncRNAs knock-down in single-cell CRISPRi screening using a new sparse supervised autoencoder neural network

Truchi,

Lacoux,

Gille

et al. 2024

Front. Bioinform.

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Single-cell CRISPR-based transcriptome screens are potent genetic tools for concomitantly assessing the expression profiles of cells targeted by a set of guides RNA (gRNA), and inferring target gene functions from the observed perturbations. However, due to various limitations, this approach lacks sensitivity in detecting weak perturbations and is essentially reliable when studying master regulators such as transcription factors. To overcome the challenge of detecting subtle gRNA induced transcriptomic perturbations and classifying the most responsive cells, we developed a new supervised autoencoder neural network method. Our Sparse supervised autoencoder (SSAE) neural network provides selection of both relevant features (genes) and actual perturbed cells. We applied this method on an in-house single-cell CRISPR-interference-based (CRISPRi) transcriptome screening (CROP-Seq) focusing on a subset of long non-coding RNAs (lncRNAs) regulated by hypoxia, a condition that promote tumor aggressiveness and drug resistance, in the context of lung adenocarcinoma (LUAD). The CROP-seq library of validated gRNA against a subset of lncRNAs and, as positive controls, HIF1A and HIF2A, the 2 main transcription factors of the hypoxic response, was transduced in A549 LUAD cells cultured in normoxia or exposed to hypoxic conditions during 3, 6 or 24 h. We first validated the SSAE approach on HIF1A and HIF2 by confirming the specific effect of their knock-down during the temporal switch of the hypoxic response. Next, the SSAE method was able to detect stable short hypoxia-dependent transcriptomic signatures induced by the knock-down of some lncRNAs candidates, outperforming previously published machine learning approaches. This proof of concept demonstrates the relevance of the SSAE approach for deciphering weak perturbations in single-cell transcriptomic data readout as part of CRISPR-based screening.

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“…CRISPRko will often be ineffective for lncRNAs as the cutting may not alter lncRNA stability or function. Several CRISPR-dCas9-based activation (CRISPRa) and inhibition (CRISPRi) screens have successfully been used to overexpress and knockdown mRNA and lncRNAs [8][9][10][11] . However, given that lncRNA transcription is often initiated from enhancer elements encoded in DNA, it is not clear whether the observed CRISPRi/a effect is DNA or RNA mediated.…”

Section: Introductionmentioning

confidence: 99%

CRISPR-Cas13d screens identifyKILR, a breast cancer risk-associated lncRNA that regulates DNA replication and repair

Wang,

Bitar,

et al. 2023

Preprint

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Long noncoding RNAs (lncRNAs) have surpassed the number of protein-coding genes, yet the majority have no known function. We previously discovered >800 lncRNAs at regions identified by breast cancer genome-wide association studies (GWAS). Here, we performed a pooled CRISPR-Cas13d RNA knockdown screen to identify which of these lncRNAs altered cell proliferation. We found thatKILR,a lncRNA that functions as a tumor suppressor, safeguards breast cells against uncontrolled proliferation. The half-life ofKILRis significantly reduced by the risk haplotype, revealing an alternative mechanism by which variants alter cancer risk. We showed thatKILRsequesters RPA1, a subunit of the RPA complex, required for DNA replication and repair. ReducedKILRexpression promotes cell proliferation by increasing the available pool of RPA1 and the speed of DNA replication. Our findings confirm lncRNAs as mediators of breast cancer risk, emphasize the need to annotate noncoding transcripts in relevant cell types when investigating GWAS variants and provide a scalable platform for mapping phenotypes associated with lncRNAs.

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Multi-hallmark long noncoding RNA maps reveal non-small cell lung cancer vulnerabilities

Cited by 15 publications

References 117 publications

“Crosstalk between non-coding RNAs and transcription factor LRF in non-small cell lung cancer”

“Crosstalk between non-coding RNAs and transcription factor LRF in non-small cell lung cancer”

Detecting subtle transcriptomic perturbations induced by lncRNAs knock-down in single-cell CRISPRi screening using a new sparse supervised autoencoder neural network

CRISPR-Cas13d screens identifyKILR, a breast cancer risk-associated lncRNA that regulates DNA replication and repair

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