NRF2-dependent Epigenetic Regulation can Promote the Hybrid Epithelial/Mesenchymal Phenotype

Jia, Wen; Jolly, Mohit Kumar; Levine, Herbert

doi:10.3389/fcell.2021.828250

Cited by 3 publications

(2 citation statements)

References 36 publications

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“…Three teams of players have been proposed to give rise to three distinct phenotypes, for instance, in the case of CD4+ T cell differentiation, where the three master regulators (and their corresponding team members) inhibit each other, driving Th1, Th2, and Th17 phenotypes ( Zhu et al, 2010 ; Duddu et al, 2020 ). Another reason underlying the higher stability of hybrid E/M phenotypes may be cell–cell communication ( Jolly et al, 2015 ) and/or epigenetic regulations ( Jia et al, 2021 ), both of which have not been included in our analysis.…”

Section: Discussionmentioning

confidence: 99%

Landscape of epithelial–mesenchymal plasticity as an emergent property of coordinated teams in regulatory networks

Hari

Ullanat²,

Balasubramanian

et al. 2022

eLife

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Elucidating the design principles of regulatory networks driving cellular decision-making has fundamental implications in mapping and eventually controlling cell-fate decisions. Despite being complex, these regulatory networks often only give rise to a few phenotypes. Previously, we identified two 'teams' of nodes in a small cell lung cancer regulatory network that constrained the phenotypic repertoire and aligned strongly with the dominant phenotypes obtained from network simulations (Chauhan et al., 2021). However, it remained elusive whether these 'teams' exist in other networks, and how do they shape the phenotypic landscape. Here, we demonstrate that five different networks of varying sizes governing epithelial-mesenchymal plasticity comprised of two 'teams' of players - one comprised of canonical drivers of epithelial phenotype and the other containing the mesenchymal inducers. These 'teams' are specific to the topology of these regulatory networks and orchestrate a bimodal phenotypic landscape with the epithelial and mesenchymal phenotypes being more frequent and dynamically robust to perturbations, relative to the intermediary/hybrid epithelial/ mesenchymal ones. Our analysis reveals that network topology alone can contain information about corresponding phenotypic distributions, thus obviating the need to simulate them. We propose 'teams' of nodes as a network design principle that can drive cell-fate canalization in diverse decision-making processes.

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Section: Discussionmentioning

confidence: 99%

Landscape of epithelial–mesenchymal plasticity as an emergent property of coordinated teams in regulatory networks

Hari

Ullanat²,

Balasubramanian

et al. 2022

eLife

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View full text Add to dashboard Cite

show abstract

“…Three teams of players have been proposed to give rise to three distinct phenotypes, for instance, in the case of CD4+ T cell differentiation, where the three master regulators (and their corresponding team members) inhibit each other, driving Th1, Th2, and Th17 phenotypes (Zhu et al, 2010, Duddu et al, 2020). Another reason underlying the higher stability of hybrid E/M phenotypes may be cell-cell communication (Jolly et al, 2015) and/or epigenetic regulations(Jia et al, 2022), both of which have not been included in our analysis.…”

Section: Discussionmentioning

confidence: 99%

Landscape of Epithelial Mesenchymal Plasticity as an emergent property of coordinated teams in regulatory networks

Hari

Ullanat²,

Balasubramanian

et al. 2021

Preprint

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Elucidating the principles of cellular decision-making is of fundamental importance. These decisions are often orchestrated by underlying regulatory networks. While we understand the dynamics of simple network motifs, how do large networks lead to a limited number of phenotypes, despite their complexity, remains largely elusive. Here, we investigate five different networks governing epithelial-mesenchymal plasticity and identified a latent design principles in their topology that limits their phenotypic repertoire - the presence of two 'teams' of nodes engaging in a mutually inhibitory feedback loop, forming a toggle switch. These teams are specific to these networks and directly shape the phenotypic landscape and consequently the frequency and stability of terminal phenotypes vs. the intermediary ones. Our analysis reveals that network topology alone can contain information about phenotypic distributions it can lead to, thus obviating the need to simulate them. We unravel topological signatures that can drive canalization of cell-fates during diverse decision-making processes.

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Polyphenols of Natural Origin Against Age-Related Disorders of Tissue Homeostasis

Голубев,

Губарева,

Анисимов

et al. 2023

Успехи Геронтологии

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Возрастные нарушения тканевого гомеостаза могут приводить к избыточной пролиферации клеток в виде опухолей и к разрастанию внеклеточного вещества в виде фиброзов. Снижает смертность и от того, и от другого, по эпидемиологическим данным, повышение содержания полифенолов (ПФ) в диете, включая флавоноиды, стильбены, лигнаны, куркуминоиды. То есть самые разные по структуре ПФ однонаправленно влияют на противоположные стороны баланса в тканевом гомеостазе: численность клеток, способных к пролиферации, и количество межклеточного вещества, не способного к ней. Общими для фиброзов и злокачественного роста являются трансформация фибробластов в миофибробласты (МФ) и эпителиально- и эндотелиально-мезенхимальные переходы клеток (ЭМП и ЭндМП) со сдвигом соотношения между клетками в сторону МФ. Усиленная способность МФ секретировать коллаген способствует фиброзу неопухолевой ткани, а ЭМП способствуют злокачественной прогрессии. На эти процессы влияют не сами ПФ, действуя на разные стерически соответствующие мишени, а продукты окисления ПФ, которые химически все являются сильными электрофилами. Связываясь с SH-группами цистеинов белка KEAP1 в комплексе с белком NRF2, они высвобождают NRF2, более всего известный как транскрипционный активатор генов, вовлеченных в антиоксидантную защиту. В настоящем обзоре внимание обращено на способность NRF2 препятствовать действию трансформирующего фактора роста-β1, которое усиливает превращение фибробластов в МФ и способствует ЭМП и ЭндМП, то есть повышает фенотипическую нестабильность клеток. Таким образом, действие ПФ против и канцерогенеза, и фиброзов может включать стабилизацию фенотипического состояния клеток, что может вносить вклад и в геропротекторное действие ПФ. Aging-related disorders of tissue homeostasis may lead to excessive cell proliferation in the form of cancer and to extracellular matrix expansion in the form of fibroses. Death rates attributed to both of the conditions are decreased, according to epidemiological evidence, upon increased dietary intakes of polyphenols, including flavonoids, stilbenes, lignans, and curcuminoids. That is, polyphenols, although they have very different structures, unidirectionally influence the two opposite sides of balance in tissue homeostasis: the cells, which are able, and the extracellular matrix, which is unable to proliferate. The common features of fibroses and cancer are the transformation of fibroblasts into myofi-broblasts (MF) and the epithelialand endothelial-to-mesenchymal transitions (EMT and EndMT), which shift cell proportions in tissues toward MF. The increased ability of MF to produce collagen promotes fibroses in non-cancerous tissues, and EMT and EndMT enhance cancer progression. These processes are influenced by not polyphenols themselves due to their interactions with different sterically suitable targets, but by polyphenol oxidation products, which are all highly electrophilic. By binding to the SH-groups of the KEAP1 protein complexed with the NRF2 protein, they release NRF2, which is generally known as a transcription factor involved in activating the genes implicated in cell antioxidant defenses. In the present review, attention is drawn to the published data about NRF2 ability to attenuate TGFβ1 signaling, which promotes fibroblasts conversion into MF and enhances EMP and EndMP, that is increases the phenotypic instability of cells. Thus, the anticarcinogenic and antifibrotic effects of polyphenols may both involve cell phenotype stabilization, which may contribute to the geroprotector effects of polyphenols.

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NRF2-dependent Epigenetic Regulation can Promote the Hybrid Epithelial/Mesenchymal Phenotype

Cited by 3 publications

References 36 publications

Landscape of epithelial–mesenchymal plasticity as an emergent property of coordinated teams in regulatory networks

Landscape of epithelial–mesenchymal plasticity as an emergent property of coordinated teams in regulatory networks

Landscape of Epithelial Mesenchymal Plasticity as an emergent property of coordinated teams in regulatory networks

Polyphenols of Natural Origin Against Age-Related Disorders of Tissue Homeostasis

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