Dynamic self-reinforcement of gene expression determines acquisition of cellular mechanical memory

Price, Christopher C.; Mathur, Jairaj; Boerckel, Joel D.; Pathak, Amit; Shenoy, Vivek B.

doi:10.1016/j.bpj.2021.10.006

Cited by 38 publications

(23 citation statements)

References 72 publications

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“…Third, by not considering cell division events, we have excluded the role of cell cycle in epigenetic regulation [64]. Fourth, we do not consider the impact of any extracellular changes during EMT such as increased matrix stiffness, which can give rise to mechanical memory due to mechanochemical feedback loops [65][66][67]. Fifth, regulatory network of a process, in general, is embedded in a larger pool with other genes/ regulatory players, and therefore its dynamics also depend on the local density of interconnections with players not directly involved in the process [68].…”

Section: Discussionmentioning

confidence: 99%

Epigenetic memory acquired during long-term EMT induction governs the recovery to the epithelial state

Jain

Corbo

Mohammad

et al. 2023

J. R. Soc. Interface.

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Epithelial–mesenchymal transition (EMT) and its reverse mesenchymal–epithelial transition (MET) are critical during embryonic development, wound healing and cancer metastasis. While phenotypic changes during short-term EMT induction are reversible, long-term EMT induction has been often associated with irreversibility. Here, we show that phenotypic changes seen in MCF10A cells upon long-term EMT induction by TGF β need not be irreversible, but have relatively longer time scales of reversibility than those seen in short-term induction. Next, using a phenomenological mathematical model to account for the chromatin-mediated epigenetic silencing of the miR-200 family by ZEB family, we highlight how the epigenetic memory gained during long-term EMT induction can slow the recovery to the epithelial state post-TGF β withdrawal. Our results suggest that epigenetic modifiers can govern the extent and time scale of EMT reversibility and advise caution against labelling phenotypic changes seen in long-term EMT induction as ‘irreversible’.

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Section: Discussionmentioning

confidence: 99%

Epigenetic memory acquired during long-term EMT induction governs the recovery to the epithelial state

Jain

Corbo

Mohammad

et al. 2023

J. R. Soc. Interface.

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“…We found that extended feedback arrest prior to reattachment, either by transcription inhibition or YAP/TAZ depletion, altered subsequent cell morphodynamics. This history-dependence is distinct from YAP/TAZ-mediated mechanical memory (Mathur et al, 2020; Nasrollahi et al, 2017; Price et al, 2021; Yang et al, 2014b), but suggests that mechanotransduction is non-linear, and features, at minimum, second order feedback dynamics.…”

Section: Discussionmentioning

confidence: 87%

Mechanotransductive feedback control of endothelial cell motility and vascular morphogenesis

Mason

Goeckel

Vega

et al. 2022

Preprint

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Vascular morphogenesis requires persistent endothelial cell motility that is responsive to diverse and dynamic mechanical stimuli. Here, we interrogated the mechanotransductive feedback dynamics that govern endothelial cell motility and vascular morphogenesis. We show that the transcriptional regulators, YAP and TAZ, are activated by mechanical cues to transcriptionally limit cytoskeletal and focal adhesion maturation, forming a conserved mechanotransductive feedback loop that mediates human endothelial cell motility in vitro and zebrafish intersegmental vessel (ISV) morphogenesis in vivo. This feedback loop closes in 4 hours, achieving cytoskeletal equilibrium in 8 hours. Feedback loop inhibition arrested endothelial cell migration in vitro and ISV morphogenesis in vivo. Inhibitor washout at 3 hrs, prior to feedback loop closure, restored vessel growth, but washout at 8 hours, longer than the feedback timescale, did not, establishing lower and upper bounds for feedback kinetics in vivo. Mechanistically, YAP and TAZ induced transcriptional suppression of myosin II activity to maintain dynamic cytoskeletal equilibria. Together, these data establish the mechanoresponsive dynamics of a transcriptional feedback loop necessary for persistent endothelial cell migration and vascular morphogenesis.

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“…Third, by not considering cell division events, we have excluded the role of cell cycle in epigenetic regulation (Nashun et al, 2015). Fourth, we do not consider the impact of any extracellular changes during EMT such as increased matrix stiffness, which can give rise to mechanical memory due to mechanochemical feedback loops (Deng et al, 2021; Kumar et al, 2014; Price et al, 2021). Nonetheless, our model was able to – a) provide insight into how the dynamics of epigenetic changes during and post EMT induction can affect the reversibility to an epithelial cell state, corroborating with existing quantitative experimental and theoretical analysis; and b) explain experimentally observed timescale differences for EMT reversibility when cells were exposed to varying duration of TGFβ treatments of varying duration.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic memory acquired during long-term EMT induction governs the recovery to the epithelial state

Jain

Corbo

Mohammad

et al. 2022

Preprint

View full text Add to dashboard Cite

Epithelial-Mesenchymal Transition (EMT) and its reverse Mesenchymal-Epithelial Transition (MET) are critical during embryonic development, wound healing and cancer metastasis. While phenotypic changes during short-term EMT induction are reversible, long-term EMT induction has been often associated with irreversibility. Here, we show that phenotypic changes seen in MCF10A cells upon long-term EMT induction by TGFβ need not be irreversible, but have relatively longer timescales of reversibility than those seen in short-term induction. Next, using a phenomenological mathematical model incorporating the epigenetic silencing of miR-200 by ZEB, we highlight how the epigenetic memory gained during long-term EMT induction can slow the recovery to the epithelial state post-TGFβ withdrawal. Our results suggest that epigenetic modifiers can govern the extent and timescale of EMT reversibility, and advise caution against labelling phenotypic changes seen in long-term EMT induction as 'irreversible'.

show abstract

Dynamic self-reinforcement of gene expression determines acquisition of cellular mechanical memory

Cited by 38 publications

References 72 publications

Epigenetic memory acquired during long-term EMT induction governs the recovery to the epithelial state

Epigenetic memory acquired during long-term EMT induction governs the recovery to the epithelial state

Mechanotransductive feedback control of endothelial cell motility and vascular morphogenesis

Epigenetic memory acquired during long-term EMT induction governs the recovery to the epithelial state

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