Biology subjects

Vancura, A.

Publications and source records attributed to Vancura, A..

5 recordsLinked to original sources

bioRxiv2022

Transcription factors interact with RNA to regulate genes

Transcription factors (TFs) orchestrate the gene expression programs that define each cells identity. The canonical TF accomplishes this with two domains, one that binds specific DNA sequences and the other that binds protein coactivators or corepressors. We find that at least half of TFs also bind RNA, doing so through a previously unrecognized domain with sequence and functional features analogous to the arginine-rich motif of the HIV transcriptional activator Tat. RNA-binding contributes to TF function by promoting the dynamic association between DNA, RNA and TF on chromatin. TF-RNA interactions are a conserved feature essential for vertebrate development and disrupted in disease. We propose that the ability to bind DNA, RNA and protein is a general property of many TFs and is fundamental to their gene regulatory function.

molecular biology↗

bioRxiv2022

Is evolutionary conservation a useful predictor for cancer long noncoding RNAs? Insights from the Cancer lncRNA Census 3

Evolutionary conservation is a measure of gene functionality that is widely used to prioritise long noncoding RNAs (lncRNA) in cancer research. Intriguingly, while updating our Cancer LncRNA Census, we observed an inverse relationship between year of discovery and evolutionary conservation. This observation is specific to cancer over other diseases, implying a sampling bias in selection of lncRNA candidates and casting doubt on the value of evolutionary metrics for prioritisation of cancer-related lncRNAs.

cancer biology↗

bioRxiv2021

Tumour mutations in long noncoding RNAs that enhance cell fitness

Long noncoding RNAs (lncRNAs) can act as tumour suppressors or oncogenes to repress/promote tumour cell proliferation via RNA-dependent mechanisms. Recently, genome sequencing has identified elevated densities of tumour somatic single nucleotide variants (SNVs) in lncRNA genes. However, this has been attributed to phenotypically-neutral "passenger" processes, and the existence of positively-selected fitness-altering "driver" SNVs acting via lncRNAs has not been addressed. We developed and used ExInAtor2, an improved driver-discovery pipeline, to map pancancer and cancer-specific mutated lncRNAs across an extensive cohort of 2583 primary and 3527 metastatic tumours. The 54 resulting lncRNAs are mostly linked to cancer for the first time. Their significance is supported by a range of clinical and genomic evidence, and display oncogenic potential when experimentally expressed in matched tumour models. Our results revealed a striking SNV hotspot in the iconic NEAT1 oncogene, which was ascribed by previous studies to passenger processes. To directly evaluate the functional significance of NEAT1 SNVs, we used in cellulo mutagenesis to introduce tumour-like mutations in the gene and observed a consequent increase in cell proliferation in both transformed and normal backgrounds. Mechanistic analyses revealed that SNVs alter NEAT1 ribonucleoprotein assembly and boost subnuclear paraspeckles. This is the first experimental evidence that mutated lncRNAs can contribute to the pathological fitness of tumour cells.

genomics↗

bioRxiv2021

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

Long noncoding RNAs (lncRNAs) are widely dysregulated in cancer, yet their functional roles in cellular disease hallmarks remain unclear. Here we employ pooled CRISPR deletion to perturb all 831 lncRNAs in KRAS-mutant non-small cell lung cancer (NSCLC), and measure their contribution to proliferation, chemoresistance and migration across two cell backgrounds. Integrative analysis of this data outperforms conventional "dropout" screens in identifying cancer genes, while prioritising disease-relevant lncRNAs with pleiotropic and background-independent roles. Altogether 60 high-confidence oncogenic lncRNAs are active in NSCLC, the majority identified here for the first time, and which tend to be amplified and overexpressed in tumours. A follow-up antisense oligonucleotide (ASO) screen shortlisted two candidates, Cancer Hallmarks in Lung LncRNA (CHiLL 1&2), whose knockdown consistently suppressed cancer hallmarks in a variety of 2D and 3D tumour models. Molecular phenotyping reveals that CHiLL 1&2 control cellular-level phenotypes via distinct transcriptional networks converging on common oncogenic pathways. In summary, this work reveals a multi-dimensional functional lncRNA landscape underlying NSCLC that contains potential therapeutic vulnerabilities.

genomics↗

bioRxiv2020

Semi-automated annotation of known and novel cancer long noncoding RNAs with the Cancer LncRNA Census 2 (CLC2)

Long noncoding RNAs play key roles in cancer and are at the vanguard of precision therapeutic development. These efforts depend on large and high-confidence collections of cancer lncRNAs. Here we present the Cancer LncRNA Census 2 (CLC2): at 492 cancer lncRNAs, it is 4-fold greater than its predecessor, without compromising on strict criteria of confident functional / genetic roles and inclusion in the GENCODE annotation scheme. This increase was enabled by leveraging high-throughput transposon insertional mutagenesis (TIM) screening data, yielding 95 novel cancer lncRNAs. CLC2 makes a valuable addition to existing collections: it is amongst the largest, holds the greatest number of unique genes, and carries functional labels (oncogene / tumour suppressor). Analysis of this dataset reveals that cancer lncRNAs are impacted by germline variants, somatic mutations, and changes in expression consistent with inferred disease functions. Furthermore, we show how clinical / genomic features can be used to vet prospective gene sets from high-throughput sources. The combination of size and quality makes CLC2 a foundation for precision medicine, demonstrating cancer lncRNAs evolutionary and clinical significance.

cancer biology↗