Sequencing of Argonaute-bound miRNA/mRNA hybrids reveals regulation of the unfolded protein response by microRNA-320a

Fields, Christopher J.; Lü, Li; Hiers, Nicholas M.; Li, Tianqi; Sheng, Peike; Huda, Taha I.; Shan, Jixiu; Gu, Tongjun; Bian, Jiang; Kilberg, Michael S.; Renne, Rolf; Xie, Mingyi

doi:10.1101/2021.10.05.463240

Cited by 4 publications

(2 citation statements)

References 98 publications

(170 reference statements)

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“…Fig 11). Previous studies reported a correlation between the number of detected hybrids and the expression levels of its miRNA and mRNA components [14,24]. These correlations hold true for our matching total and the small RNA-seq data when taking the total count across the replicates (Fig 4 .B, left panels).…”

Section: Contribution Of Mirnas To the Resistant Phenotypesupporting

confidence: 79%

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A multi-omics integrative approach unravels novel genes and pathways associated with senescence escape after targeted therapy in NRAS mutant melanoma

Gureghian

Herbst

Kozar

et al. 2023

Preprint

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Therapy Induced Senescence (TIS) leads to sustained growth arrest of cancer cells. Conversely, the Senescence Associated Secretory Phenotype (SASP) has been shown to promote tumorigenesis and metastasis. The associated cytostasis, which was first conceived as permanent, has since been shown to be reversible. Cells escaping senescence further enhance the aggressiveness of cancers. Despite all this, the mechanisms by which cancer cells escape senescence are poorly understood and the development of specific and efficient 'senolytics', specifically targeting senescent cancer cells, is in its infancy. Together with targeted therapeutics, senolytics constitute a promising avenue for improved cancer treatments. Understanding how cancer cells evade senescence is needed to optimize the clinical benefits of this promising approach. Here we characterized the response of three different NRAS mutant melanoma cell lines to a combination of CDK4/6 and MEK inhibitors over 33 days. Transcriptomic data show that all cell lines trigger a senescence program coupled with strong induction of interferons. Kinome profiling revealed the activation of Receptor Tyrosine Kinases (RTKs) and enriched downstream signaling of neurotrophin, ErbB and insulin pathways. Characterization of the miRNA interactome associates miR-211-5p with resistant phenotypes. Finally, integration of bulk and single-cell RNA-seq data identified biological processes perturbed during senescence establishment and escape, and predicts new genes involved in this shift. Overall, our data associate insulin signaling with persistence of a senescent phenotype and suggest a new role for interferon gamma in senescence escape through the induction of EMT and the activation of ERK5 signaling.

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Section: Contribution Of Mirnas To the Resistant Phenotypesupporting

confidence: 79%

“…Fig 12). Previous studies reported a correlation between the number of detected hybrids and the expression levels of its miRNA and mRNA components [15,31].…”

Section: Contribution Of Mirnas To the Resistant Phenotypementioning

confidence: 95%

A multi-omics integrative approach unravels novel genes and pathways associated with senescence escape after targeted therapy in NRAS mutant melanoma

Gureghian

Herbst

Kozar

et al. 2023

Preprint

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Widespread microRNA degradation elements in target mRNAs can assist the encoded proteins

Sheng

et al. 2021

Genes Dev.

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Binding of microRNAs (miRNAs) to mRNAs normally results in post-transcriptional repression of gene expression. However, extensive base-pairing between miRNAs and target RNAs can trigger miRNA degradation, a phenomenon called target RNA-directed miRNA degradation (TDMD). Here, we systematically analyzed Argonaute-CLASH (cross-linking, ligation, and sequencing of miRNA–target RNA hybrids) data and identified numerous candidate TDMD triggers, focusing on their ability to induce nontemplated nucleotide addition at the miRNA 3′ end. When exogenously expressed in various cell lines, eight triggers induce degradation of corresponding miRNAs. Both the TDMD base-pairing and surrounding sequences are essential for TDMD. CRISPR knockout of endogenous trigger or ZSWIM8, a ubiquitin ligase essential for TDMD, reduced miRNA degradation. Furthermore, degradation of miR-221 and miR-222 by a trigger in BCL2L11, which encodes a proapoptotic protein, enhances apoptosis. Therefore, we uncovered widespread TDMD triggers in target RNAs and demonstrated an example that could functionally cooperate with the encoded protein.

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MicroRNAs as the Sentinels of Redox and Hypertrophic Signalling

Kolodziej

Burns

Goljanek‐Whysall

2022

IJMS

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Oxidative stress and inflammation are associated with skeletal muscle function decline with ageing or disease or inadequate exercise and/or poor diet. Paradoxically, reactive oxygen species and inflammatory cytokines are key for mounting the muscular and systemic adaptive responses to endurance and resistance exercise. Both ageing and lifestyle-related metabolic dysfunction are strongly linked to exercise redox and hypertrophic insensitivity. The adaptive inability and consequent exercise intolerance may discourage people from physical training resulting in a vicious cycle of under-exercising, energy surplus, chronic mitochondrial stress, accelerated functional decline and increased susceptibility to serious diseases. Skeletal muscles are malleable and dynamic organs, rewiring their metabolism depending on the metabolic or mechanical stress resulting in a specific phenotype. Endogenous RNA silencing molecules, microRNAs, are regulators of these metabolic/phenotypic shifts in skeletal muscles. Skeletal muscle microRNA profiles at baseline and in response to exercise have been observed to differ between adult and older people, as well as trained vs. sedentary individuals. Likewise, the circulating microRNA blueprint varies based on age and training status. Therefore, microRNAs emerge as key regulators of metabolic health/capacity and hormetic adaptability. In this narrative review, we summarise the literature exploring the links between microRNAs and skeletal muscle, as well as systemic adaptation to exercise. We expand a mathematical model of microRNA burst during adaptation to exercise through supporting data from the literature. We describe a potential link between the microRNA-dependent regulation of redox-signalling sensitivity and the ability to mount a hypertrophic response to exercise or nutritional cues. We propose a hypothetical model of endurance exercise-induced microRNA “memory cloud” responsible for establishing a landscape conducive to aerobic as well as anabolic adaptation. We suggest that regular aerobic exercise, complimented by a healthy diet, in addition to promoting mitochondrial health and hypertrophic/insulin sensitivity, may also suppress the glycolytic phenotype and mTOR signalling through miRNAs which in turn promote systemic metabolic health.

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Sequencing of Argonaute-bound miRNA/mRNA hybrids reveals regulation of the unfolded protein response by microRNA-320a

Cited by 4 publications

References 98 publications

A multi-omics integrative approach unravels novel genes and pathways associated with senescence escape after targeted therapy in NRAS mutant melanoma

A multi-omics integrative approach unravels novel genes and pathways associated with senescence escape after targeted therapy in NRAS mutant melanoma

Widespread microRNA degradation elements in target mRNAs can assist the encoded proteins

MicroRNAs as the Sentinels of Redox and Hypertrophic Signalling

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