Multi-omics analysis reveals contextual tumor suppressive and oncogenic gene modules within the acute hypoxic response

AbstractCellular adaptation to hypoxia is a hallmark of cancer, but the relative contribution of hypoxia-inducible factors (HIFs) versus other oxygen sensors to tumorigenesis is unclear. We employ a multi-omics pipeline including measurements of nascent RNA to characterize transcriptional changes upon acute hypoxia. We identify an immediate early transcriptional response that is strongly dependent on HIF1A and the kinase activity of its cofactor CDK8, includes indirect repression of MYC targets, and is highly conserved across cancer types. HIF1A drives this acute response via conserved high-occupancy enhancers. Genetic screen data indicates that, in normoxia, HIF1A displays strong cell-autonomous tumor suppressive effects through a gene module mediating mTOR inhibition. Conversely, in advanced malignancies, expression of a module of HIF1A targets involved in collagen remodeling is associated with poor prognosis across diverse cancer types. In this work, we provide a valuable resource for investigating context-dependent roles of HIF1A and its targets in cancer biology.

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Role of long interspersed nuclear element-1 in the regulation of chromatin landscapes and genome dynamics

Experimental Biology and Medicine ◽

10.1177/15353702211031247 ◽

2021 ◽

pp. 153537022110312

Author(s):

Kenneth S Ramos ◽

Pasano Bojang ◽

Emma Bowers

Keyword(s):

Cancer Biology ◽

Mobile Element ◽

Cancer Diagnostics ◽

Regulatory Control ◽

Full Potential ◽

Genome Dynamics ◽

Human Illness ◽

Cancer Types ◽

Stressful Environments

LINE-1 retrotransposon, the most active mobile element of the human genome, is subject to tight regulatory control. Stressful environments and disease modify the recruitment of regulatory proteins leading to unregulated activation of LINE-1. The activation of LINE-1 influences genome dynamics through altered chromatin landscapes, insertion mutations, deletions, and modulation of cellular plasticity. To date, LINE-1 retrotransposition has been linked to various cancer types and may in fact underwrite the genetic basis of various other forms of chronic human illness. The occurrence of LINE-1 polymorphisms in the human population may define inter-individual differences in susceptibility to disease. This review is written in honor of Dr Peter Stambrook, a friend and colleague who carried out highly impactful cancer research over many years of professional practice. Dr Stambrook devoted considerable energy to helping others live up to their full potential and to navigate the complexities of professional life. He was an inspirational leader, a strong advocate, a kind mentor, a vocal supporter and cheerleader, and yes, a hard critic and tough friend when needed. His passionate stand on issues, his witty sense of humor, and his love for humanity have left a huge mark in our lives. We hope that that the knowledge summarized here will advance our understanding of the role of LINE-1 in cancer biology and expedite the development of innovative cancer diagnostics and treatments in the ways that Dr Stambrook himself had so passionately envisioned.

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Transcriptional Changes in Potato Sprouts upon Interaction with Rhizoctonia solani Indicate Pathogen-Induced Interference in the Defence Pathways of Potato

International Journal of Molecular Sciences ◽

10.3390/ijms22063094 ◽

2021 ◽

Vol 22 (6) ◽

pp. 3094

Author(s):

Rita Zrenner ◽

Bart Verwaaijen ◽

Franziska Genzel ◽

Burkhardt Flemer ◽

Rita Grosch

Keyword(s):

Rhizoctonia Solani ◽

Rna Sequencing ◽

Control Strategies ◽

Transcriptional Response ◽

Black Scurf ◽

Post Inoculation ◽

Molecular Response ◽

Resistance Level ◽

Sequencing Experiment ◽

Transcriptional Changes

Rhizoctonia solani is the causer of black scurf disease on potatoes and is responsible for high economical losses in global agriculture. In order to increase the limited knowledge of the plants’ molecular response to this pathogen, we inoculated potatoes with R. solani AG3-PT isolate Ben3 and carried out RNA sequencing with total RNA extracted from potato sprouts at three and eight days post inoculation (dpi). In this dual RNA-sequencing experiment, the necrotrophic lifestyle of R. solani AG3-PT during early phases of interaction with its host has already been characterised. Here the potato plants’ comprehensive transcriptional response to inoculation with R. solani AG3 was evaluated for the first time based on significantly different expressed plant genes extracted with DESeq analysis. Overall, 1640 genes were differentially expressed, comparing control (−Rs) and with R. solani AG3-PT isolate Ben3 inoculated plants (+Rs). Genes involved in the production of anti-fungal proteins and secondary metabolites with antifungal properties were significantly up regulated upon inoculation with R. solani. Gene ontology (GO) terms involved in the regulation of hormone levels (i.e., ethylene (ET) and jasmonic acid (JA) at 3 dpi and salicylic acid (SA) and JA response pathways at 8 dpi) were significantly enriched. Contrastingly, the GO term “response to abiotic stimulus” was down regulated at both time points analysed. These results may support future breeding efforts toward the development of cultivars with higher resistance level to black scurf disease or the development of new control strategies.

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Criticality in tumor evolution and clinical outcome

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1807256115 ◽

2018 ◽

Vol 115 (47) ◽

pp. E11101-E11110 ◽

Cited By ~ 11

Author(s):

Erez Persi ◽

Yuri I. Wolf ◽

Mark D. M. Leiserson ◽

Eugene V. Koonin ◽

Eytan Ruppin

Keyword(s):

Clinical Outcome ◽

Cancer Biology ◽

Patient Survival ◽

Fitness Landscape ◽

Purifying Selection ◽

Nonlinear Effects ◽

Tumor Evolution ◽

Evolutionary Trajectories ◽

Cancer Types ◽

Selection Phase

How mutation and selection determine the fitness landscape of tumors and hence clinical outcome is an open fundamental question in cancer biology, crucial for the assessment of therapeutic strategies and resistance to treatment. Here we explore the mutation-selection phase diagram of 6,721 tumors representing 23 cancer types by quantifying the overall somatic point mutation load (ML) and selection (dN/dS) in the entire proteome of each tumor. We show that ML strongly correlates with patient survival, revealing two opposing regimes around a critical point. In low-ML cancers, a high number of mutations indicates poor prognosis, whereas high-ML cancers show the opposite trend, presumably due to mutational meltdown. Although the majority of cancers evolve near neutrality, deviations are observed at extreme MLs. Melanoma, with the highest ML, evolves under purifying selection, whereas in low-ML cancers, signatures of positive selection are observed, demonstrating how selection affects tumor fitness. Moreover, different cancers occupy specific positions on the ML–dN/dS plane, revealing a diversity of evolutionary trajectories. These results support and expand the theory of tumor evolution and its nonlinear effects on survival.

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A Bayesian Nonparametric Approach to Discover Clinico-Genetic Associations across Cancer Types

10.1101/623215 ◽

2019 ◽

Author(s):

Melanie F. Pradier ◽

Stephanie L. Hyland ◽

Stefan G. Stark ◽

Kjong Lehmann ◽

Julia E. Vogt ◽

...

Keyword(s):

Cancer Biology ◽

Multiple Hypothesis Testing ◽

Environmental Data ◽

Bayesian Nonparametric ◽

Genetic Associations ◽

Disease Treatment ◽

Nonparametric Approach ◽

Gene Level ◽

Cancer Types ◽

Unsupervised Approach

AbstractMotivationPersonalized medicine aims at combining genetic, clinical, and environmental data to improve medical diagnosis and disease treatment, tailored to each patient. This paper presents a Bayesian nonparametric (BNP) approach to identify genetic associations with clinical/environmental features in cancer. We propose an unsupervised approach to generate data-driven hypotheses and bring potentially novel insights about cancer biology. Our model combines somatic mutation information at gene-level with features extracted from the Electronic Health Record. We propose a hierarchical approach, the hierarchical Poisson factor analysis (H-PFA) model, to share information across patients having different types of cancer. To discover statistically significant associations, we combine Bayesian modeling with bootstrapping techniques and correct for multiple hypothesis testing.ResultsUsing our approach, we empirically demonstrate that we can recover well-known associations in cancer literature. We compare the results of H-PFA with two other classical methods in the field: case-control (CC) setups, and linear mixed models (LMMs).

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Fasting promotes acute hypoxic adaptation by suppressing mTOR-mediated pathways

Cell Death and Disease ◽

10.1038/s41419-021-04351-x ◽

2021 ◽

Vol 12 (11) ◽

Author(s):

Ruzhou Zhao ◽

Xingcheng Zhao ◽

Xiaobo Wang ◽

Yanqi Liu ◽

Jie Yang ◽

...

Keyword(s):

Acute Hypoxia ◽

Survival Rates ◽

The Body ◽

Utilization Efficiency ◽

Ros Generation ◽

Oxygen Utilization ◽

Mtor Inhibition ◽

Atp Production ◽

Hypoxic Adaptation ◽

Hypoxic Tolerance

AbstractRapid adaptation to a hypoxic environment is an unanswered question that we are committed to exploring. At present, there is no suitable strategy to achieve rapid hypoxic adaptation. Here, we demonstrate that fasting preconditioning for 72 h reduces tissue injuries and maintains cardiac function, consequently significantly improving the survival rates of rats under extreme hypoxia, and this strategy can be used for rapid hypoxic adaptation. Mechanistically, fasting reduces blood glucose and further suppresses tissue mTOR activity. On the one hand, fasting-induced mTOR inhibition reduces unnecessary ATP consumption and increases ATP reserves under acute hypoxia as a result of decreased protein synthesis and lipogenesis; on the other hand, fasting-induced mTOR inhibition improves mitochondrial oxygen utilization efficiency to ensure ATP production under acute hypoxia, which is due to the significant decrease in ROS generation induced by enhanced mitophagy. Our findings highlight the important role of mTOR in acute hypoxic adaptation, and targeted regulation of mTOR could be a new strategy to improve acute hypoxic tolerance in the body.

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Schlafens: Emerging Proteins in Cancer Cell Biology

Cells ◽

10.3390/cells10092238 ◽

2021 ◽

Vol 10 (9) ◽

pp. 2238

Author(s):

Sarmad Al-Marsoummi ◽

Emilie E. Vomhof-DeKrey ◽

Marc D. Basson

Keyword(s):

Cell Proliferation ◽

Cell Growth ◽

Cell Biology ◽

Cancer Biology ◽

Immune Cell ◽

Biological Functions ◽

Cancer Types ◽

Opposing Effects ◽

High Degree ◽

Human And Mouse

Schlafens (SLFN) are a family of genes widely expressed in mammals, including humans and rodents. These intriguing proteins play different roles in regulating cell proliferation, cell differentiation, immune cell growth and maturation, and inhibiting viral replication. The emerging evidence is implicating Schlafens in cancer biology and chemosensitivity. Although Schlafens share common domains and a high degree of homology, different Schlafens act differently. In particular, they show specific and occasionally opposing effects in some cancer types. This review will briefly summarize the history, structure, and non-malignant biological functions of Schlafens. The roles of human and mouse Schlafens in different cancer types will then be outlined. Finally, we will discuss the implication of Schlafens in the anti-tumor effect of interferons and the use of Schlafens as predictors of chemosensitivity.

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Gene by environmental interactions affecting oxidative phosphorylation and thermal sensitivity

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00008.2016 ◽

2016 ◽

Vol 311 (1) ◽

pp. R157-R165 ◽

Cited By ~ 13

Author(s):

Tara Z. Baris ◽

Pierre U. Blier ◽

Nicolas Pichaud ◽

Douglas L. Crawford ◽

Marjorie F. Oleksiak

Keyword(s):

Oxidative Phosphorylation ◽

Complex I ◽

Thermal Sensitivity ◽

Single Species ◽

Mitochondrial Haplotype ◽

Acclimation Temperature ◽

Atp Production ◽

Acute Response ◽

Relative Contribution ◽

Mitochondrial Genotype

The oxidative phosphorylation (OxPhos) pathway is responsible for most aerobic ATP production and is the only metabolic pathway with proteins encoded by both nuclear and mitochondrial genomes. In studies examining mitonuclear interactions among distant populations within a species or across species, the interactions between these two genomes can affect metabolism, growth, and fitness, depending on the environment. However, there is little data on whether these interactions impact natural populations within a single species. In an admixed Fundulus heteroclitus population with northern and southern mitochondrial haplotypes, there are significant differences in allele frequencies associated with mitochondrial haplotype. In this study, we investigate how mitochondrial haplotype and any associated nuclear differences affect six OxPhos parameters within a population. The data demonstrate significant OxPhos functional differences between the two mitochondrial genotypes. These differences are most apparent when individuals are acclimated to high temperatures with the southern mitochondrial genotype having a large acute response and the northern mitochondrial genotype having little, if any acute response. Furthermore, acute temperature effects and the relative contribution of Complex I and II depend on acclimation temperature: when individuals are acclimated to 12°C, the relative contribution of Complex I increases with higher acute temperatures, whereas at 28°C acclimation, the relative contribution of Complex I is unaffected by acute temperature change. These data demonstrate a complex gene by environmental interaction affecting the OxPhos pathway.

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Glucocorticoid-dependent transcription in skin requires epidermal expression of the glucocorticoid receptor and is modulated by the mineralocorticoid receptor

Scientific Reports ◽

10.1038/s41598-020-75853-5 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Lisa M. Sevilla ◽

Judit Bigas ◽

Álvaro Chiner-Oms ◽

Iñaki Comas ◽

Vicente Sentandreu ◽

...

Keyword(s):

Gene Expression ◽

Mineralocorticoid Receptor ◽

Inflammatory Diseases ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Transcriptional Response ◽

Specific Loss ◽

Relative Contribution ◽

Effective Use ◽

Epidermal Expression

Abstract Glucocorticoid (GC) actions are mediated through two closely related ligand-dependent transcription factors, the GC receptor (GR) and the mineralocorticoid receptor (MR). Given the wide and effective use of GCs to combat skin inflammatory diseases, it is important to understand the relative contribution of these receptors to the transcriptional response to topical GCs. We evaluated the gene expression profiles in the skin of mice with epidermal-specific loss of GR (GREKO), MR (MREKO), or both (double KO; DKO) in response to dexamethasone (Dex). The overall transcriptional response was abolished in GREKO and DKO skin suggesting dependence of the underlying dermis on the presence of epidermal GR. Indeed, the observed dermal GC resistance correlated with a constitutive decrease in GR activity and up-regulation of p38 activity in this skin compartment. Upon Dex treatment, more than 90% of differentially expressed genes (DEGs) in CO overlapped with MREKO. However, the number of DEGs was fourfold increased and the magnitude of response was higher in MREKO vs CO, affecting both gene induction and repression. Taken together our data reveal that, in the cutaneous transcriptional response to GCs mediated through endogenous receptors, epidermal GR is mandatory while epidermal MR acts as a chief modulator of gene expression.

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Integrated Dissection of lncRNA-Perturbated Triplets Reveals Novel Prognostic Signatures Across Cancer Types

International Journal of Molecular Sciences ◽

10.3390/ijms21176087 ◽

2020 ◽

Vol 21 (17) ◽

pp. 6087

Author(s):

Yunzhen Wei ◽

Limeng Zhou ◽

Yingzhang Huang ◽

Dianjing Guo

Keyword(s):

Cancer Biology ◽

Noncoding Rna ◽

The Cancer Genome Atlas ◽

Dynamic Changes ◽

Computational Framework ◽

Potential Biomarker ◽

Cancer Genome Atlas ◽

Cancer Types ◽

Tcga Dataset ◽

Pan Cancer

Long noncoding RNA (lncRNA)/microRNA(miRNA)/mRNA triplets contribute to cancer biology. However, identifying significative triplets remains a major challenge for cancer research. The dynamic changes among factors of the triplets have been less understood. Here, by integrating target information and expression datasets, we proposed a novel computational framework to identify the triplets termed as “lncRNA-perturbated triplets”. We applied the framework to five cancer datasets in The Cancer Genome Atlas (TCGA) project and identified 109 triplets. We showed that the paired miRNAs and mRNAs were widely perturbated by lncRNAs in different cancer types. LncRNA perturbators and lncRNA-perturbated mRNAs showed significantly higher evolutionary conservation than other lncRNAs and mRNAs. Importantly, the lncRNA-perturbated triplets exhibited high cancer specificity. The pan-cancer perturbator OIP5-AS1 had higher expression level than that of the cancer-specific perturbators. These lncRNA perturbators were significantly enriched in known cancer-related pathways. Furthermore, among the 25 lncRNA in the 109 triplets, lncRNA SNHG7 was identified as a stable potential biomarker in lung adenocarcinoma (LUAD) by combining the TCGA dataset and two independent GEO datasets. Results from cell transfection also indicated that overexpression of lncRNA SNHG7 and TUG1 enhanced the expression of the corresponding mRNA PNMA2 and CDC7 in LUAD. Our study provides a systematic dissection of lncRNA-perturbated triplets and facilitates our understanding of the molecular roles of lncRNAs in cancers.

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Reeling in the Zebrafish Cancer Models

Annual Review of Cancer Biology ◽

10.1146/annurev-cancerbio-051320-014135 ◽

2020 ◽

Vol 5 (1) ◽

Author(s):

Alicia M. McConnell ◽

Haley R. Noonan ◽

Leonard I. Zon

Keyword(s):

Cancer Biology ◽

Model Organism ◽

Transgenic Animals ◽

Annual Review ◽

Transgenic Zebrafish ◽

Publication Date ◽

Cancer Therapies ◽

Cancer Models ◽

Cancer Types ◽

New Cancer Therapies

Zebrafish are rapidly becoming a leading model organism for cancer research. The genetic pathways driving cancer are highly conserved between zebrafish and humans, and the ability to easily manipulate the zebrafish genome to rapidly generate transgenic animals makes zebrafish an excellent model organism. Transgenic zebrafish containing complex, patient-relevant genotypes have been used to model many cancer types. Here we present a comprehensive review of transgenic zebrafish cancer models as a resource to the field and highlight important areas of cancer biology that have yet to be studied in the fish. The ability to image cancer cells and niche biology in an endogenous tumor make zebrafish an indispensable model organism in which we can further understand the mechanisms that drive tumorigenesis and screen for potential new cancer therapies. Expected final online publication date for the Annual Review of Cancer Biology, Volume 5 is March 4, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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