Browsing by Author "Jia, Wen"

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    NRF2-dependent Epigenetic Regulation can Promote the Hybrid Epithelial/Mesenchymal Phenotype
    (Frontiers Media S.A., 2022) Jia, Wen; Jolly, Mohit Kumar; Levine, Herbert
    The epithelial-mesenchymal transition (EMT) is a cellular process critical for wound healing, cancer metastasis and embryonic development. Recent efforts have identified the role of hybrid epithelial/mesenchymal states, having both epithelial and mesehncymal traits, in enabling cancer metastasis and resistance to various therapies. Also, previous work has suggested that NRF2 can act as phenotypic stability factor to help stablize such hybrid states. Here, we incorporate a phenomenological epigenetic feedback effect into our previous computational model for EMT signaling. We show that this type of feedback can stabilize the hybrid state as compared to the fully mesenchymal phenotype if NRF2 can influence SNAIL at an epigenetic level, as this link makes transitions out of hybrid state more difficult. However, epigenetic regulation on other NRF2-related links do not significantly change the EMT dynamics. Finally, we considered possible cell division effects in our epigenetic regulation model, and our results indicate that the degree of epigenetic inheritance does not appear to be a critical factor for the hybrid E/M state stabilizing behavior of NRF2.
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    The Modeling of Epigenetics and Its Regulation in EMT/MET
    (2022-04-21) Jia, Wen; Onuchic, José Nelson; Levine, Herbert; Kolomeisky, Anatoly Boris
    The epithelial-mesenchymal transition (EMT) plays an important role in cancer metastasis and drug resistance, and involves epigenetic remodeling. However, how epigenetic changes affect the dynamical traits such as plasticity or memory is not fully understood. In this thesis, we analyze the effects of epigenetic feedback on EMT through integrating the effects of this feedback on various aspects of the miR-200/ZEB loop – a core circuit regulating EMT. Epigenetic feedback on the inhibition of miR-200 by ZEB can largely stabilize the mesenchymal state, thus making the process irreversible. Follow-up preliminary experiments show that when EMT is induced in epithelial cells, a certain percentage of cells can stay in the mesenchymal state even after the inducing signal is removed. This percentage depends on the extent of induction of EMT, thus well recapitulating our model-based predictions. Beyond the irreversibility of EMT, we also investigate the irreversibility of MET, or equivalently, resistance to EMT. We identify the epigenetic regulation acting on the ZEB1/GRHL2 link as a key determinant of driving an irreversible MET. Furthermore, we focus on the E/M hybrid state, and show that it can be stabilized as compared to the fully mesenchymal phenotype if NRF2 can influence SNAIL at an epigenetic level, as this link makes transitions out of hybrid state more difficult. Finally, we explore a general feature of the observed multi-stability, the lack of correlation between landscape and corresponding transition rates.