MYC dosage compensation is mediated by miRNA-transcription factor interactions in aneuploid cancer

Acón, ManSai; Geiß, Carsten; Jorge, Torres-Calvo; Bravo-Estupiñan, Diana M.; Guillermo, Oviedo; Arias-Arias, Jorge L.; Rojas-Matey, Luis A.; Baez, Edwin; Vásquez-Vargas, Gloriana; Oses-Vargas, Yendry; Guevara-Coto, José; Segura-Castillo, Andrés; Siles, F.; Quirós-Barrantes, Steve; Régnier‐Vigouroux, Anne; Mendes, Pedro; Mora-Rodríguez, Rodrigo

doi:10.1016/j.isci.2021.103407

Cited by 8 publications

(28 citation statements)

References 89 publications

(103 reference statements)

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“…To explore this possibility, we constructed a network of experimentally validated interactions from several databases using the miRNAs and transcription factors cited above and reported to be involved in macrophage activation. We constructed the network using our recently published biocomputational platform BioNetUCR [61]. The resulting network is highly complex, including 148 transcription factors, 24 miRNAs, and 537 genes (not shown).…”

Section: Mirna Circuits As Possible Sources Of Bistability In Gene Ex...mentioning

confidence: 99%

Multistability in Macrophage Activation Pathways and Metabolic Implications

Geiß

Salas

Guevara-Coto

et al. 2022

Cells

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Macrophages are innate immune cells with a dynamic range of reversible activation states including the classical pro-inflammatory (M1) and alternative anti-inflammatory (M2) states. Deciphering how macrophages regulate their transition from one state to the other is key for a deeper understanding of inflammatory diseases and relevant therapies. Common regulatory motifs reported for macrophage transitions, such as positive or double-negative feedback loops, exhibit a switchlike behavior, suggesting the bistability of the system. In this review, we explore the evidence for multistability (including bistability) in macrophage activation pathways at four molecular levels. First, a decision-making module in signal transduction includes mutual inhibitory interactions between M1 (STAT1, NF-KB/p50-p65) and M2 (STAT3, NF-KB/p50-p50) signaling pathways. Second, a switchlike behavior at the gene expression level includes complex network motifs of transcription factors and miRNAs. Third, these changes impact metabolic gene expression, leading to switches in energy production, NADPH and ROS production, TCA cycle functionality, biosynthesis, and nitrogen metabolism. Fourth, metabolic changes are monitored by metabolic sensors coupled to AMPK and mTOR activity to provide stability by maintaining signals promoting M1 or M2 activation. In conclusion, we identify bistability hubs as promising therapeutic targets for reverting or blocking macrophage transitions through modulation of the metabolic environment.

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Section: Mirna Circuits As Possible Sources Of Bistability In Gene Ex...mentioning

confidence: 99%

Multistability in Macrophage Activation Pathways and Metabolic Implications

Geiß

Salas

Guevara-Coto

et al. 2022

Cells

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“…In our previous work, 71 we implemented a similar approach to CNV-buffering capacity of Hose et al to identify dosage-compensated genes. We began with the NCI60 human cancer cell lines given the amount of information available for evaluation and comparison, in which investigators worked with gene copy numbers, genic expression, and proteomics.…”

Section: Genes Under Dosage Compensationmentioning

confidence: 99%

“…Potential regulation at the RNA level [71] Partial correlation between copy number and RNA expression while controlling for tumor purity.…”

Section: Candidate Genes Including 7 Transcription Factorsmentioning

confidence: 99%

Gene dosage compensation: Origins, criteria to identify compensated genes, and mechanisms including sensor loops as an emerging systems‐level property in cancer

Bravo‐Estupiñan,

Aguilar‐Guerrero,

Quirós

et al. 2023

Cancer Medicine

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The gene dosage compensation hypothesis presents a mechanism through which the expression of certain genes is modulated to compensate for differences in the dose of genes when additional chromosomes are present. It is one of the means through which cancer cells actively cope with the potential damaging effects of aneuploidy, a hallmark of most cancers. Dosage compensation arises through several processes, including downregulation or overexpression of specific genes and the relocation of dosage‐sensitive genes. In cancer, a majority of compensated genes are generally thought to be regulated at the translational or post‐translational level, and include the basic components of a compensation loop, including sensors of gene dosage and modulators of gene expression. Post‐translational regulation is mostly undertaken by a general degradation or aggregation of remaining protein subunits of macromolecular complexes. An increasingly important role has also been observed for transcriptional level regulation. This article reviews the process of targeted gene dosage compensation in cancer and other biological conditions, along with the mechanisms by which cells regulate specific genes to restore cellular homeostasis. These mechanisms represent potential targets for the inhibition of dosage compensation of specific genes in aneuploid cancers. This article critically examines the process of targeted gene dosage compensation in cancer and other biological contexts, alongside the criteria for identifying genes subject to dosage compensation and the intricate mechanisms by which cells orchestrate the regulation of specific genes to reinstate cellular homeostasis. Ultimately, our aim is to gain a comprehensive understanding of the intricate nature of a systems‐level property. This property hinges upon the kinetic parameters of regulatory motifs, which we have termed “gene dosage sensor loops.” These loops have the potential to operate at both the transcriptional and translational levels, thus emerging as promising candidates for the inhibition of dosage compensation in specific genes. Additionally, they represent novel and highly specific therapeutic targets in the context of aneuploid cancer.

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“…To explore this possibility, we constructed a network of experimentally validated interactions from several databases using the list of miRNAs and transcription factors cited above and reported to be involved in macrophage activation. We constructed the network using our recently published biocomputational platform BioNetUCR [63]. The resulting network is highly complex including 148 transcription factors, 24 miRNAs and 537 genes (not shown).…”

Section: Mirna Circuits As Possible Sources Of Bistability In Gene Expressionmentioning

confidence: 99%

Bistability in macrophage polarization and metabolic implications

Geiß¹,

Salas²,

Guevara-Coto³

et al. 2021

Preprint

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Macrophages are essential innate immune cells characterized by a high diversity and plasticity. In vitro, their full dynamic range of activation profiles include the classical pro-inflammatory (M1) and the alternative anti-inflammatory (M2) program. Bistability usually arises in biological systems that contain a positive-feedback loop or a mutually inhibitory, double-negative-feedback loop, which are common regulatory motifs reported for macrophage transitions from one activation state to the other one. This switch-like behavior of macrophage is observed at four different levels. First, a decision-making module in signal transduction includes mutual inhibitory interactions between M1 (STAT1 and NF-KB/p50-p65) and M2 (STAT3 and NF-KB/p50-p50) signaling pathways. Second, a switch-like behavior at the gene expression level includes complex network motifs of transcription factors and miRNAs. Third, those changes impact metabolic gene expression leading to several switches in energy production, NADPH and ROS production, TCA cycle functionality, biosynthesis and nitrogen metabolism. Fourth, metabolic changes are monitored by specialized metabolic sensors coupled to AMPK and mTOR activity to provide stability by maintaining the signals to promote either M1 or M2 activation. The targeting of robust molecular switches has the potential to treat a broad range of widespread diseases such as sepsis, cancer or chronic inflammatory diseases.

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MYC dosage compensation is mediated by miRNA-transcription factor interactions in aneuploid cancer

Cited by 8 publications

References 89 publications

Multistability in Macrophage Activation Pathways and Metabolic Implications

Multistability in Macrophage Activation Pathways and Metabolic Implications

Gene dosage compensation: Origins, criteria to identify compensated genes, and mechanisms including sensor loops as an emerging systems‐level property in cancer

Bistability in macrophage polarization and metabolic implications

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