Aina Maria Mas

BACKGROUND: It is now obvious that the majority of cellular transcripts do not code for proteins, and a significant subset of them are long non-coding RNAs (lncRNAs). Many lncRNAs show aberrant expression in cancer, and some of them have been linked to cell transformation. However, the underlying mechanisms remain poorly understood and it is unknown how the sequences of lncRNA dictate their function. RESULTS: Here we characterize the function of the p53-regulated human lncRNA LINC-PINT in cancer. We find that LINC-PINT is downregulated in multiple types of cancer and acts as a tumor suppressor lncRNA by reducing the invasive phenotype of cancer cells. A cross-species analysis identifies a highly conserved sequence element in LINC-PINT that is essential for its function. This sequence mediates a specific interaction with PRC2, necessary for the LINC-PINT-dependent repression of a pro-invasion signature of genes regulated by the transcription factor EGR1. CONCLUSIONS: Our findings support a conserved functional co-dependence between LINC-PINT and PRC2 and lead us to propose a new mechanism where the lncRNA regulates the availability of free PRC2 at the proximity of co-regulated genomic loci.

Cells must coordinate the activation of thousands of replication origins dispersed throughout their genome. Active transcription is known to favor the formation of mammalian origins, although the role that RNA plays in this process remains unclear. We show that the ORC1 subunit of the human Origin Recognition Complex interacts with RNAs transcribed from genes with origins in their transcription start sites (TSSs), displaying a positive correlation between RNA binding and origin activity. RNA depletion, or the use of ORC1 RNA-binding mutant, result in inefficient activation of proximal origins, linked to impaired ORC1 chromatin release. ORC1 RNA binding activity resides in its intrinsically disordered region, involved in intra- and inter-molecular interactions, regulation by phosphorylation, and phase-separation. We show that RNA binding favors ORC1 chromatin release, by regulating its phosphorylation and subsequent degradation. Our results unveil a non-coding function of RNA as a dynamic component of the chromatin, orchestrating the activation of replication origins.

Article Tools UNDERSTANDING THE PATHWAY Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES Long Noncoding RNA Expression Independently Predicts Outcome in Pediatric Acute Myeloid Leukemia. February 16, 2023 ARTICLE CITATION DOI: 10.1200/JCO.23.00381 Journal of Clinical Oncology - published online before print April 12, 2023 PMID: 37043713 Long Noncoding RNA Signatures as Cancer Biomarkers Aina M. Mas , PhD1,2xAina M. MasSearch for articles by this author and Maite Huarte , PhD1,2xMaite HuarteSearch for articles by this author Show More 1Center for Applied Medical Research, University of Navarra, Pamplona, Spain2Institute of Health Research of Navarra (IdiSNA), Pamplona, Spain https://doi.org/10.1200/JCO.23.00381 First Page Full Text PDF Figures and Tables © 2023 by American Society of Clinical OncologySUPPORTSupported by PID2020-113683GB-100/funded by MCIN/AEI/10.13039/501100011033, La Caixa Foundation (LCF/PR/HR21/00176), European Research Council Consolidator 771425, and Worldwide Cancer Research 20-0204 grants (M.H.); and Ministerio de Economía y Competitividad REF: BES2015-074569 cofounded by FSE (A.M.M.).AUTHOR CONTRIBUTIONSConception and design: All authorsManuscript writing: All authorsFinal approval of manuscript: All authorsAccountable for all aspects of the work: All authorsAUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTERESTLong Noncoding RNA Signatures as Cancer BiomarkersThe following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).No potential conflicts of interest were reported. Companion Long Noncoding RNA Expression Independently Predicts Outcome in Pediatric Acute Myeloid Leukemia

Long non-coding RNAs (lncRNAs) play fundamental roles in cellular processes and pathologies, regulating gene expression at multiple levels. Despite being highly cell type-specific, their study at single-cell (sc) level is challenging due to their less accurate annotation and low expression compared to protein-coding genes. Here, we systematically benchmark different preprocessing methods and develop a computational framework, named ELATUS, based on the combination of the pseudoaligner Kallisto with selective functional filtering. ELATUS enhances the detection of functional lncRNAs from scRNA-seq data, detecting their expression with higher concordance than standard methods with the ATAC-seq profiles in single-cell multiome data. Interestingly, the better results of ELATUS are due to its advanced performance with an inaccurate reference annotation such as that of lncRNAs. We independently confirm the expression patterns of cell type-specific lncRNAs exclusively detected with ELATUS and unveil biologically important lncRNAs, such as AL121895.1, a previously undocumented cis-repressor lncRNA, whose role in breast cancer progression is unnoticed by traditional methodologies. Our results emphasize the necessity for an alternative scRNA-seq workflow tailored to lncRNAs that sheds light on the multifaceted roles of lncRNAs. The inaccurate annotation of long noncoding RNAs (lncRNAs) hampers their detection by scRNA-seq. The computational workflow ELATUS, based on the pseudoaligner Kallisto, addresses this problem and uncovers functional lncRNAs, such as AL121895.1, that participates in breast cancer.