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Publications about 'transcription factors'
Articles in journal or book chapters
and E.D. Sontag.
Immunobiochemical reconstruction of influenza lung infection - melanoma skin cancer interactions.
Frontiers in Immunology,
Recent experimental results from the Zloza lab combined a mouse model of influenza A virus (IAV) infection (A/H1N1/PR8) and a highly aggressive model of infection-unrelated cancer, B16-F10 skin melanoma. This paper showed that acute influenza infection of the lung promotes distal melanoma growth in the dermis of the flank and leads to decreased host survival. Here, we proceed to ground the experimental observations in a mechanistic immunobiochemical model that incorporates the T cell receptor signaling pathway, various transcription factors, and a gene regulatory network (GRN). A core component of our model is a biochemical motif, which we call a Triple Incoherent Feed-Forward Loop (TIFFL), and which reflects known interactions between IRF4, Blimp-1, and Bcl-6. The different activity levels of the TIFFL components, as a function of the cognate antigen levels and the given inflammation context, manifest themselves in phenotypically distinct outcomes. Specifically, both the TIFFL reconstruction and quantitative estimates obtained from the model allowed us to formulate a hypothesis that it is the loss of the fundamental TIFFL-induced adaptation of the expression of PD-1 receptors on anti-melanoma CD8+ T cells that constitutes the essence of the previously unrecognized immunologic factor that promotes the experimentally observed distal tumor growth in the presence of acute non-ocogenic infection. We therefore hope that this work can further highlight the importance of adaptive mechanisms by which immune functions contribute to the balance between self and non-self immune tolerance, adaptive resistance, and the strength of TCR-induced activation, thus contributing to the understanding of a broader complexity of fundamental interactions between pathogens and tumors.
and A. Levine.
The P53HMM algorithm: using novel profile Hidden Markov Models to detect p53-responsive genes.
Keyword(s): Hidden Markov Models,
A novel computational method (called p53HMM) is presented that utilizes Profile Hidden Markov Models (PHMM's) to estimate the relative binding affinities of putative p53 response elements (RE's), both p53 single-sites and cluster-sites. These models incorporate a novel ``Correlated Baum Welch'' training algorithm that provides increased predictive power by exploiting the redundancy of information found in the repeated, palindromic p53-binding motif. The predictive accuracy of these new models are compared against other predictive models, including position specic score matrices (PSSM's, or weight matrices). Finally, we provide experimental evidence that verifies a predicted p53-target site that regu- lates the CHMP4C gene. The P53HMM algorithm is available on-line from http://tools.csb.ias.edu.
and D. Del Vecchio.
Stochastic analysis of genetic feedback controllers to reprogram a pluripotency gene regulatory network.
In Proc. 2019 Automatic Control Conference,
Note: To appear.[PDF]
chemical master equations.
Cellular reprogramming is traditionally accomplished through an open loop control approach, wherein key transcription factors are injected in cells to steer a gene regulatory network toward a pluripotent state. Recently, a closed loop feedback control strategy was proposed in order to achieve more accurate control. Previous analyses of the controller were based on deterministic models, ignoring the substantial stochasticity in these networks, Here we analyze the Chemical Master Equation for reaction models with and without the feedback controller. We computationally and analytically investigate the performance of the controller in biologically relevant parameter regimes where stochastic effects dictate system dynamics. Our results indicate that the feedback control approach still ensures reprogramming even when analyzed using a stochastic model.
M. A. Al-Radhawi,
and E. D. Sontag.
A mathematical model exhibiting the effect of DNA methylation on the stability boundary in cell-fate networks.
Cold Spring Harbor Laboratory,
Note: BioRxiv preprint 10.1101/2019.12.19.883280.
Keyword(s): Cell-fate networks,
gene regulatory networks,
pluripotent stem cell circuit.
Cell-fate networks are traditionally studied within the framework of gene regulatory networks. This paradigm considers only interactions of genes through expressed transcription factors and does not incorporate chromatin modification processes. This paper introduces a mathematical model that seamlessly combines gene regulatory networks and DNA methylation, with the goal of quantitatively characterizing the contribution of epigenetic regulation to gene silencing. The ``Basin of Attraction percentage'' is introduced as a metric to quantify gene silencing abilities. As a case study, a computational and theoretical analysis is carried out for a model of the pluripotent stem cell circuit as well as a simplified self-activating gene model. The results confirm that the methodology quantitatively captures the key role that methylation plays in enhancing the stability of the silenced gene state.
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