Non-CG DNA methylation is a biomarker for assessing endodermal differentiation capacity in pluripotent stem cells

Butcher, Lee M.; Ito, Mitsuteru; Brimpari, Minodora; Morris, Tiffany; Soares, Filipa; Ährlund‐Richter, Lars; Carey, Nessa; Vallier, Ludovic; Ferguson‐Smith, Anne C.; Beck, Stephan

doi:10.1038/ncomms10458

Cited by 41 publications

(48 citation statements)

References 47 publications

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“…Several regulatory mechanisms of ERK translocation have also been proposed [14,34,35]. ERK-mediated phosphorylation of NPC reduces the nuclear accumulation of importin-beta that transports several proteins, including ERK, from the cytoplasm to the nucleus [34,35], suggesting that activated ERK may potentially regulate its own translocation.…”

Section: Modelmentioning

confidence: 99%

“…ERK-mediated phosphorylation of NPC reduces the nuclear accumulation of importin-beta that transports several proteins, including ERK, from the cytoplasm to the nucleus [34,35], suggesting that activated ERK may potentially regulate its own translocation. In addition, we recently demonstrated that ERK-mediated phosphorylation of NPC is involved in the switch-like behavior of nuclear ERK translocation [14]. Based on these biological findings, we developed a new mathematical model to describe ERK translocation (S1C Fig).…”

Section: Modelmentioning

confidence: 99%

“…EGF ligands bind to EGF receptors (EGFR), and the signal is transmitted to an intracellular biochemical reaction network. This signal transduction eventually phosphorylates extracellular signal-regulated kinase (ERK) and causes transient accumulation of ERK at the nucleus [13,14]. The EGF dose response of phosphorylated ERK shows a graded response [10,15–17].…”

Section: Introductionmentioning

confidence: 99%

“…The EGF dose response of phosphorylated ERK shows a graded response [10,15–17]. However, it was recently reported that the dose response of nuclear ERK activity is in fact switch-like [14]; a threshold mechanism regulated by ERK may be involved in cell fate decision. The switch-like behavior is more sensitive to perturbations than the graded response [18], and hence the effect of biological noise is considered to be critical to determine nuclear ERK activity.…”

Section: Introductionmentioning

confidence: 99%

“…The switch-like behavior is more sensitive to perturbations than the graded response [18], and hence the effect of biological noise is considered to be critical to determine nuclear ERK activity. In fact, heterogeneous cell responses in nuclear ERK have been observed [13,14]. To determine how such heterogeneity in nuclear ERK response is evoked, we performed mathematical modeling and simulation analysis of the EGF signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

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Modeling Cellular Noise Underlying Heterogeneous Cell Responses in the Epidermal Growth Factor Signaling Pathway

Iwamoto¹,

Shindo²,

Takahashi

2016

PLoS Comput Biol

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Cellular heterogeneity, which plays an essential role in biological phenomena, such as drug resistance and migration, is considered to arise from intrinsic (i.e., reaction kinetics) and extrinsic (i.e., protein variability) noise in the cell. However, the mechanistic effects of these types of noise to determine the heterogeneity of signal responses have not been elucidated. Here, we report that the output of epidermal growth factor (EGF) signaling activity is modulated by cellular noise, particularly by extrinsic noise of particular signaling components in the pathway. We developed a mathematical model of the EGF signaling pathway incorporating regulation between extracellular signal-regulated kinase (ERK) and nuclear pore complex (NPC), which is necessary for switch-like activation of the nuclear ERK response. As the threshold of switch-like behavior is more sensitive to perturbations than the graded response, the effect of biological noise is potentially critical for cell fate decision. Our simulation analysis indicated that extrinsic noise, but not intrinsic noise, contributes to cell-to-cell heterogeneity of nuclear ERK. In addition, we accurately estimated variations in abundance of the signal proteins between individual cells by direct comparison of experimental data with simulation results using Apparent Measurement Error (AME). AME was constant regardless of whether the protein levels varied in a correlated manner, while covariation among proteins influenced cell-to-cell heterogeneity of nuclear ERK, suppressing the variation. Simulations using the estimated protein abundances showed that each protein species has different effects on cell-to-cell variation in the nuclear ERK response. In particular, variability of EGF receptor, Ras, Raf, and MEK strongly influenced cellular heterogeneity, while others did not. Overall, our results indicated that cellular heterogeneity in response to EGF is strongly driven by extrinsic noise, and that such heterogeneity results from variability of particular protein species that function as sensitive nodes, which may contribute to the pathogenesis of human diseases.

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