Here, we employed a targeted single-cell RNA-seq approach to reveal lncRNAs differentially expressed in blood leukocytes during severe COVID-19.
Although long non-coding RNAs (lncRNAs) have been suggested as important regulators of transcription factor activity, their contributions to the systemic immunopathologies observed during SARS-CoV-2 infection have remained unknown. The systemic immune response to viral infection is shaped by master transcription factors such as NFκB or PU.1. Finally, we explore other examples of cytoskeletal lncRNAs currently unrelated to tumorigenesis, to illustrate knowledge about them. In this review, we summarize current information available about the roles of lncRNAs as modulators of actin dependent cytoskeleton and their impact on cancer pathogenesis. Recently, many reports have pointed out that lncRNAs could be critical mediators in cellular homeostasis controlling dynamic structure and stability of the network formed by cytoskeletal structures, specifically in different types of carcinomas. Loss of cytoskeleton homeostasis and integrity of cell focal adhesion are hallmarks of several cancer types. Furthermore, the cytoskeleton is subject to intense spatio-temporal regulation mediated by the assembly and disassembly of its components. Interaction between these protein structures is essential for the cytoskeletal mesh to be functional. Broadly, the cytoskeleton consists of three types of structural proteins: (1) actin filaments, involved in establishing and maintaining cell shape and movement (2) microtubules, necessary to support the different organelles and distribution of chromosomes during cell cycle and (3) intermediate filaments, which have a mainly structural function showing specificity for the cell type where they are expressed. The importance of the cytoskeleton not only in cell architecture but also as a pivotal element in the transduction of signals that mediate multiple biological processes has recently been highlighted. This review provides insight into the molecular and cellular mechanisms involved in the development of resistance during the treatment of OS and discusses promising novel therapies (e.g., afatinib and palbociclib) for overcoming resistance to chemotherapy in OS. Moreover, microRNAs may act as predictors of drug resistance in OS. This approach has shown that other therapies, along with standard chemotherapy, can improve responses to therapy in patients with OS. This versatility of cells to generate chemoresistance has motivated the use of anti-angiogenic therapy based on tyrosine kinase inhibitors. Molecular and cellular mechanisms associated with resistance to chemotherapy include DNA repair and cell-cycle alterations, enhanced drug efflux, increased detoxification, resistance to apoptosis, autophagy, tumor extracellular matrix, and angiogenesis. The main reason for the poor outcomes in patients with OS is the development of resistance to methotrexate, cisplatin, doxorubicin, and ifosfamide. Despite the availability of multimodal treatment with surgery and chemotherapy, the clinical results remain unsatisfactory. Osteosarcoma (OS) is the most common type of bone sarcoma. Our results suggest a major role of nuclear noncoding RNA networks in systemic antiviral responses to SARS-CoV-2 in humans. Alarmin expression is additionally enhanced by the up-regulation of the lncRNA LUCAT1, which promotes NF-κB–dependent gene expression at the expense of targets of the JAK-STAT pathway.
NF-κB–dependent PIRAT down-regulation during COVID-19 consequently releases a transcriptional brake, fueling alarmin production. Knockout and transgene expression, combined with chromatin-occupancy profiling, characterized PIRAT as a nuclear decoy RNA, keeping PU.1 from binding to alarmin promoters and promoting its binding to pseudogenes in naïve monocytes. Our results uncover the lncRNA PIRAT (PU.1-induced regulator of alarmin transcription) as a major PU.1 feedback-regulator in monocytes, governing the production of the alarmins S100A8/A9, key drivers of COVID-19 pathogenesis. Here, we employed a targeted single-cell RNA sequencing approach to reveal lncRNAs differentially expressed in blood leukocytes during severe COVID-19. Although long noncoding RNAs (lncRNAs) have been suggested as important regulators of transcription factor activity, their contributions to the systemic immunopathologies observed during SARS-CoV-2 infection have remained unknown. The systemic immune response to viral infection is shaped by master transcription factors, such as NF-κB, STAT1, or PU.1.
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