epigenetic instability
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2022 ◽  
Vol 23 (2) ◽  
pp. 830
Author(s):  
Karpiński Paweł ◽  
Sąsiadek Maria Małgorzata

The CpG island methylator phenotype (CIMP) can be regarded as the most notable emanation of epigenetic instability in cancer. Since its discovery in the late 1990s, CIMP has been extensively studied, mainly in colorectal cancers (CRC) and gliomas. Consequently, knowledge on molecular and pathological characteristics of CIMP in CRC and other tumour types has rapidly expanded. Concordant and widespread hypermethylation of multiple CpG islands observed in CIMP in multiple cancers raised hopes for future epigenetically based diagnostics and treatments of solid tumours. However, studies on CIMP in solid tumours were hampered by a lack of generalisability and reproducibility of epigenetic markers. Moreover, CIMP was not a satisfactory marker in predicting clinical outcomes. The idea of targeting epigenetic abnormalities such as CIMP for cancer therapy has not been implemented for solid tumours, either. Twenty-one years after its discovery, we aim to cover both the fundamental and new aspects of CIMP and its future application as a diagnostic marker and target in anticancer therapies.


Antioxidants ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 1553
Author(s):  
Abdelhakim Bouyahya ◽  
Naoual El Menyiy ◽  
Loubna Oumeslakht ◽  
Aicha El Allam ◽  
Abdelaali Balahbib ◽  
...  

ROS (reactive oxygen species) are produced via the noncomplete reduction in molecular oxygen in the mitochondria of higher organisms. The produced ROS are placed in various cell compartments, such as the mitochondria, cytoplasm, and endoplasmic reticulum. In general, there is an equilibrium between the synthesis of ROS and their reduction by the natural antioxidant defense system, called the redox system. Therefore, when this balance is upset, the excess ROS production can affect different macromolecules, such as proteins, lipids, nucleic acids, and sugars, which can lead to an electronic imbalance than oxidation of these macromolecules. Recently, it has also been shown that ROS produced at the cellular level can affect different signaling pathways that participate in the stimulation of transcription factors linked to cell proliferation and, consequently, to the carcinogenesis process. Indeed, ROS can activate the pathway of tyrosine kinase, MAP kinase, IKK, NF-KB, phosphoinositol 3 phosphate, and hypoxia-inducible factor (HIF). The activation of these signaling pathways directly contributes to the accelerated proliferation process and, as a result, the appearance of cancer. In addition, the use of antioxidants, especially natural ones, is now a major issue in the approach to cancer prevention. Some natural molecules, especially phytochemicals isolated from medicinal plants, have now shown interesting preclinical and clinical results.


2021 ◽  
Vol 17 (8) ◽  
pp. e1009307
Author(s):  
Anshul Saini ◽  
James M. Gallo

Drug resistance is a significant obstacle to successful and durable anti-cancer therapy. Targeted therapy is often effective during early phases of treatment; however, eventually cancer cells adapt and transition to drug-resistant cells states rendering the treatment ineffective. It is proposed that cell state can be a determinant of drug efficacy and manipulated to affect the development of anticancer drug resistance. In this work, we developed two stochastic cell state models and an integrated stochastic-deterministic model referenced to brain tumors. The stochastic cell state models included transcriptionally-permissive and -restrictive states based on the underlying hypothesis that epigenetic instability mitigates lock-in of drug-resistant states. When moderate epigenetic instability was implemented the drug-resistant cell populations were reduced, on average, by 60%, whereas a high level of epigenetic disruption reduced them by about 90%. The stochastic-deterministic model utilized the stochastic cell state model to drive the dynamics of the DNA repair enzyme, methylguanine-methyltransferase (MGMT), that repairs temozolomide (TMZ)-induced O6-methylguanine (O6mG) adducts. In the presence of epigenetic instability, the production of MGMT decreased that coincided with an increase of O6mG adducts following a multiple-dose regimen of TMZ. Generation of epigenetic instability via epigenetic modifier therapy could be a viable strategy to mitigate anticancer drug resistance.


2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Georgina E. T. Blake ◽  
Xiaohui Zhao ◽  
Hong wa Yung ◽  
Graham J. Burton ◽  
Anne C. Ferguson-Smith ◽  
...  

AbstractThe mechanism behind transgenerational epigenetic inheritance is unclear, particularly through the maternal grandparental line. We previously showed that disruption of folate metabolism in mice by the Mtrr hypomorphic mutation results in transgenerational epigenetic inheritance of congenital malformations. Either maternal grandparent can initiate this phenomenon, which persists for at least four wildtype generations. Here, we use genome-wide approaches to reveal genetic stability in the Mtrr model and genome-wide differential DNA methylation in the germline of Mtrr mutant maternal grandfathers. We observe that, while epigenetic reprogramming occurs, wildtype grandprogeny and great grandprogeny exhibit transcriptional changes that correlate with germline methylation defects. One region encompasses the Hira gene, which is misexpressed in embryos for at least three wildtype generations in a manner that distinguishes Hira transcript expression as a biomarker of maternal phenotypic inheritance.


Author(s):  
Maxfield M G Kelsey

Abstract Long Interspersed Nuclear Element-1 (LINE-1 or L1) is the only autonomously active retrotransposon in humans. While L1 has been implicated in several pathologies and the aging process, I present a model which challenges an understanding of L1 as predominantly antagonistic to human health. I hypothesize that L1 serves as a reporter in an early cancer alert system: a tripwire strung throughout the genome poised to trigger p53 and a type I interferon (IFN-1) response when the epigenetic landscape portends cancer. Cell proliferation and a shift to aerobic glycolysis cause dramatic changes in the epigenome which are permissive to L1’s escape from suppression. L1 has several properties which make it particularly apt to fulfil this hypothesized sentinel function. Being present in many copies spread throughout the genome allows it to monitor many regions for epigenetic instability and renders it robust to deactivation by mutation. This proposed cancer alert system would alter the cancer cell fitness landscape discouraging the use of growth-favoring aerobic glycolysis by threatening the activation of tumor suppressive mechanisms. It also imposes costs on a strategy of non-specific global transcriptional derepression aimed at activating oncogenes. Erroneous activations of this system are predicted to increase the rate of aging, suggesting this represents a case of antagonistic pleiotropy trading prolonged youth for cancer prevention. More research is needed to assess this model.


2021 ◽  
pp. 1-18
Author(s):  
Raman Preet Kaur ◽  
Prabhsimran Kaur ◽  
Anjana Munshi

2020 ◽  
Author(s):  
Anshul Saini ◽  
James M. Gallo

AbstractDrug resistance is a significant obstacle to successful and durable anti-cancer therapy. Targeted therapy is often effective during early phases of treatment; however, eventually cancer cells adapt and transition to drug-resistant cells states rendering the treatment ineffective. It is proposed that cell state can be a determinant of drug efficacy and manipulated to affect the development of anticancer drug resistance. In this work, we developed two stochastic cell state models – referenced to brain tumors - that included transcriptionally-permissive and -restrictive states based on the underlying hypothesis that epigenetic instability mitigates lock-in of drug-resistant states. One model used single-step state transitions, whereas the other considered a multi-step process to lock-in drug resistance. The latter model showed that with moderate epigenetic instability the drug-resistant cell populations were reduced, on average, by 60%, whereas a high level of epigenetic disruption reduced them by about 90%. Generation of epigenetic instability via epigenetic modifier therapy could be a viable strategy to mitigate anticancer drug resistance.


2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii75-ii75
Author(s):  
Kevin Johnson ◽  
Kevin Anderson ◽  
Elise Courtois ◽  
Floris Barthel ◽  
Frederick Varn ◽  
...  

Abstract Extensive intra- and intertumoral heterogeneity in glioma contributes to therapeutic resistance and poor patient outcomes. Alterations to DNA methylation (DNAme) modulate epigenetic homeostasis, allowing tumor cells to sample alternative cell states to promote tumorigenesis. However, the epigenetic mechanisms that promote cellular plasticity and regulate cell states are still poorly understood. To characterize the epigenetic mechanisms underlying glioma heterogeneity we profiled 914 single-cell methylomes, 55,284 single-cell transcriptomes, and bulk whole genomes across 11 patient samples spanning initial and recurrent time points and 3 molecular subtypes delineated by IDH mutation status. Local DNAme disorder, defined as epimutation burden, was increased in tumor cells relative to nontumor cells, higher in IDH wild-type than in IDH mutant glioma and was positively associated with copy number alteration (CNA). Epimutation was positively associated with transcriptional variability and enriched at genes involved in cellular differentiation. Epimutation was also increased in the binding sites of transcription factors (TFs) associated with response to extracellular stimuli, suggesting that stochastic DNAme alterations enable cellular plasticity and diverse responses to microenvironmental stressors. Integrative clustering of DNAme and scRNAseq profiles defined stem-like and differentiated-like cell states which exhibited differences in TF activity. Stem-like cells were enriched for differentially methylated binding sites of TFs associated with hypoxia response. scDNAme and scRNAseq-derived copy number profiles were compared with bulk copy number profiles and inferred tumor phylogenies to assess how the timing of CNAs impact epigenetic instability, with results suggesting that early CNA events propagate both genetic and epigenetic heterogeneity. Bulk longitudinal data was used to validate the relationship of epigenetic instability with CNA burden as well as differentially methylated binding sites of cell stress response TFs. Our work suggests that local DNAme disorder promotes cellular plasticity and enables adaptive response to cellular stress such as hypoxia.


Author(s):  
Kevin C. Johnson ◽  
Kevin J. Anderson ◽  
Elise T. Courtois ◽  
Floris P. Barthel ◽  
Frederick S. Varn ◽  
...  

ABSTRACTGlioma intratumoral heterogeneity enables adaptation to challenging microenvironments and contributes to universal therapeutic resistance. Here, we integrated 914 single-cell DNA methylomes, 55,284 single-cell transcriptomes, and bulk multi-omic profiles across 11 adult IDH-mutant or IDH-wild-type gliomas to delineate sources of intratumoral heterogeneity. We found that local DNA methylation instability, or epimutation burden, was elevated in more aggressive tumors, reflected intratumoral variability, linked with transcriptional disruption, and associated with environmental stress response. We show that the activation of cell-state specific transcription factors is impacted by epimutations and that loosened epigenetic control may facilitate cellular plasticity. Our analyses support that somatic copy number alterations (SCNAs) promote epigenetic instability and that SCNAs largely precede epigenetic and transcriptomic diversification during glioma evolution. We confirmed the link between genetic and epigenetic instability by analyzing larger cohorts of bulk longitudinally collected and spatially separated DNA methylation data. Increased DNA methylation instability was associated with accelerated disease progression, and recurrently selected DNA methylation changes were enriched for environmental stress response pathways. Our work provides an integrative framework to better understand glioma evolution and highlights the importance of epigenetic heterogeneity in shaping therapeutic response.


2020 ◽  
Author(s):  
Georgina E.T. Blake ◽  
Xiaohui Zhao ◽  
Hong wa Yung ◽  
Graham J. Burton ◽  
Anne C. Ferguson-Smith ◽  
...  

ABSTRACTThe mechanism behind transgenerational epigenetic inheritance (TEI) is unclear, particularly through the maternal grandparental line. We previously showed that disruption of folate metabolism in mice by the Mtrrgt hypomorphic mutation results in TEI of congenital malformations. Either maternal grandparent can initiate this phenomenon, which persists for at least four wildtype generations. In this work, we use a genome-wide approach to reveal genetic stability in the Mtrrgt model and epigenome-wide differential DNA methylation in the germline of Mtrr+/gt maternal grandfathers. While epigenetic reprogramming occurs, wildtype grandprogeny and great grandprogeny exhibit transcriptional memory of germline methylation defects. One region encompasses the Hira gene, which is misexpressed in embryos at least until the F3 generation in a manner that distinguishes Hira transcript expression as a biomarker of maternal phenotypic inheritance.


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