miRNA Combinatorics and its Role in Cell State Control—A Probabilistic Approach

Mahlab-Aviv, Shelly; Linial, Nathan; Linial, Michal

doi:10.3389/fmolb.2021.772852

Cited by 8 publications

(4 citation statements)

References 33 publications

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“…It is proposed that several of the SNHG members carry anti-inflammatory roles under oxygen-glucose deprivation/reoxygenation (OGD/R) conditions by targeting specific miRNAs [31,47]. In such cases, the ratio of free cellular miRNAs can be slightly changed, leading to a revised cell state by the available miRNA pool [48]. Our observations emphasize the importance of SNHGs beyond cancer in cell physiology and homeostasis (Figure 5).…”

Section: Cancer-related Snhg Family Members Are Differentially Expres...mentioning

confidence: 55%

Alteration in Long Noncoding RNAs in Response to Oxidative Stress and Ladostigil in SH-SY5Y Cells

Zohar¹,

Giladi²,

Eliyahu³

et al. 2022

Preprint

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Microglia activation causes neuroinflammation, which is a hallmark of neurodegenerative disorders, brain injury, and aging. Ladostigil, a bifunctional reagent with antioxidant and anti-inflammatory properties, reduced microglial activation and enhanced brain functioning in elderly rats. In this study, we studied SH-SY5Y, a human neuroblastoma cell line, and tested viability in the presence of hydrogen peroxide and Sin1 (3-morpholinosydnonimine), which generates reactive oxygen and nitrogen species (ROS/RNS). Both stressors caused significant apoptosis and necrotic cell death that was attenuated by ladostigil. Our results from RNA-seq experiments show that long non-coding RNAs (lncRNAs) account for 30% of all transcripts in SH-SY5Y cells treated with Sin1 for 24 hours. Altogether, we identify 94 differently expressed lncRNAs in the presence of Sin1, including MALAT1, a highly expressed lncRNA with anti-inflammatory and anti-apoptotic functions. Additional activities of Sin-1 upregulated lncRNAs include redox homeostasis (e.g., MIAT, GABPB1-AS1), energy metabolism (HAND2-AS1), and neurodegeneration (e.g., MIAT, GABPB1-AS1, NEAT1). Four lncRNAs implicated as enhancers were significantly upregulated in cells exposed to Sin1 and ladostigil. Finally, we show that H2O2 and Sin1 increased the expression of DJ-1, a redox sensor and modulator of Nrf2 (nuclear factor erythroid 2–related factor 2). Nrf2 (NFE2L2 gene) is a major transcription factor regulating antioxidant genes. In the presence of ladostigil, DJ-1 expression is restored to its baseline. The mechanisms governing SH-SY5Y cell survival and homeostasis are highlighted by the beneficial role of ladostigil in the crosstalk involving Nrf2, antioxidant transcription factor DJ-1, and lncRNAs. Stress-dependent induction of lncRNAs represents an underappreciated regulatory level that contributes to cellular homeostasis and the capacity of SH-SY5Y to cope with oxidative stress.

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Section: Cancer-related Snhg Family Members Are Differentially Expres...mentioning

confidence: 55%

Alteration in Long Noncoding RNAs in Response to Oxidative Stress and Ladostigil in SH-SY5Y Cells

Zohar¹,

Giladi²,

Eliyahu³

et al. 2022

Preprint

Self Cite

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show abstract

“…In addition, quantitative competition on miRNA binding sites (MBS) results from a competition on the accessibility of the targets ( Mahlab-Aviv et al, 2019 ). Such competition is governed by alterations in miRNA quantities and composition ( Mahlab-Aviv et al, 2021 ), and the presence of circular RNAs (circRNAs), pseudogenes and long ncRNAs (lncRNAs) with MBS. This paradigm is referred to as competing endogenous RNAs (ceRNAs) ( Denzler et al, 2014 ; Lai et al, 2016 ).…”

Section: Resultsmentioning

confidence: 99%

“…miRNAs play key roles in a broad range of cellular processes and the response to changes in the environment ( Leung and Sharp, 2010 ). The miRNA profile is tissue-specific and an indicator of cell identity ( Mahlab-Aviv et al, 2021 ). Their ability to maintain cell and tissue homeostasis is critical, with many miRNA genes implicated in human diseases such as metabolic, inflammatory, and neurodegenerative diseases ( Vishnoi and Rani, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Inferring microRNA regulation: A proteome perspective

Ofer

Linial

2022

Front. Mol. Biosci.

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Post-transcriptional regulation in multicellular organisms is mediated by microRNAs. However, the principles that determine if a gene is regulated by miRNAs are poorly understood. Previous works focused mostly on miRNA seed matches and other features of the 3′-UTR of transcripts. These common approaches rely on knowledge of the miRNA families, and computational approaches still yield poor, inconsistent results, with many false positives. In this work, we present a different paradigm for predicting miRNA-regulated genes based on the encoded proteins. In a novel, automated machine learning framework, we use sequence as well as diverse functional annotations to train models on multiple organisms using experimentally validated data. We present insights from tens of millions of features extracted and ranked from different modalities. We show high predictive performance per organism and in generalization across species. We provide a list of novel predictions including Danio rerio (zebrafish) and Arabidopsis thaliana (mouse-ear cress). We compare genomic models and observe that our protein model outperforms, whereas a unified model improves on both. While most membranous and disease related proteins are regulated by miRNAs, the G-protein coupled receptor (GPCR) family is an exception, being mostly unregulated by miRNAs. We further show that the evolutionary conservation among paralogs does not imply any coherence in miRNA regulation. We conclude that duplicated paralogous genes that often changed their function, also diverse in their tendency to be miRNA regulated. We conclude that protein function is informative across species in predicting post-transcriptional miRNA regulation in living cells.

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“…Similarly, NORAD promotes cell survival by sponging miRNAs [ 23 ]. In such cases, even a small change in the accessibility of miRNAs alters the ratio of free to bound cellular miRNAs, leading to a revised cell state by the available miRNA pool [ 63 ].…”

Section: Discussionmentioning

confidence: 99%

Oxidative Stress and Its Modulation by Ladostigil Alter the Expression of Abundant Long Non-Coding RNAs in SH-SY5Y Cells

Zohar

Giladi

Eliyahu

et al. 2022

ncRNA

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Neurodegenerative disorders, brain injury, and the decline in cognitive function with aging are accompanied by a reduced capacity of cells in the brain to cope with oxidative stress and inflammation. In this study, we focused on the response to oxidative stress in SH-SY5Y, a human neuroblastoma cell line. We monitored the viability of the cells in the presence of oxidative stress. Such stress was induced by hydrogen peroxide or by Sin1 (3-morpholinosydnonimine) that generates reactive oxygen and nitrogen species (ROS and RNS). Both stressors caused significant cell death. Our results from the RNA-seq experiments show that SH-SY5Y cells treated with Sin1 for 24 h resulted in 94 differently expressed long non-coding RNAs (lncRNAs), including many abundant ones. Among the abundant lncRNAs that were upregulated by exposing the cells to Sin1 were those implicated in redox homeostasis, energy metabolism, and neurodegenerative diseases (e.g., MALAT1, MIAT, GABPB1-AS1, NEAT1, MIAT, GABPB1-AS1, and HAND2-AS1). Another group of abundant lncRNAs that were significantly altered under oxidative stress included cancer-related SNHG family members. We tested the impact of ladostigil, a bifunctional reagent with antioxidant and anti-inflammatory properties, on the lncRNA expression levels. Ladostigil was previously shown to enhance learning and memory in the brains of elderly rats. In SH-SY5Y cells, several lncRNAs involved in transcription regulation and the chromatin structure were significantly induced by ladostigil. We anticipate that these poorly studied lncRNAs may act as enhancers (eRNA), regulating transcription and splicing, and in competition for miRNA binding (ceRNA). We found that the induction of abundant lncRNAs, such as MALAT1, NEAT-1, MIAT, and SHNG12, by the Sin1 oxidative stress paradigm specifies only the undifferentiated cell state. We conclude that a global alteration in the lncRNA profiles upon stress in SH-SY5Y may shift cell homeostasis and is an attractive in vitro system to characterize drugs that impact the redox state of the cells and their viability.

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miRNA Combinatorics and its Role in Cell State Control—A Probabilistic Approach

Cited by 8 publications

References 33 publications

Alteration in Long Noncoding RNAs in Response to Oxidative Stress and Ladostigil in SH-SY5Y Cells

Alteration in Long Noncoding RNAs in Response to Oxidative Stress and Ladostigil in SH-SY5Y Cells

Inferring microRNA regulation: A proteome perspective

Oxidative Stress and Its Modulation by Ladostigil Alter the Expression of Abundant Long Non-Coding RNAs in SH-SY5Y Cells

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