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A multi-scale approach reveals that NF-κB cRel enforces a B-cell decision to divide.

Shokhirev MN, Almaden J, Davis-Turak J, Birnbaum HA, Russell TM, Vargas JA, Hoffmann A - Mol. Syst. Biol. (2015)

Bottom Line: B-lymphocyte population dynamics, which are predictive of immune response and vaccine effectiveness, are determined by individual cells undergoing division or death seemingly stochastically.Combining modeling and experimentation, we found that NF-κB cRel enforces the execution of a cellular decision between mutually exclusive fates by promoting survival in growing cells.We show that a multi-scale modeling approach allows for the prediction of dynamic organ-level physiology in terms of intra-cellular molecular networks.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, Signaling Systems Laboratory, UCSD, La Jolla, CA, USA San Diego Center for Systems Biology, UCSD, La Jolla, CA, USA Bioinformatics and Systems Biology Graduate Program, UCSD, La Jolla, CA, USA.

No MeSH data available.


B cells decide to divide or die and are protected from the alternate fateA Flowchart depicting the scenario in which the cell fate of growing cells is determined by a race between division (green) and death (red); hypothetical division and death time distributions before and after mutual censorship are shown on the right.B Flowchart depicting the scenario in which entering the growth phase or not represents an early commitment to one fate; the independent division (green) and death (red) time distributions are shown on the right.C–F Analysis of response (growth), division, and death statistics for WT B cells. Error bars = 1/n. Measured generational probabilities that a growing (C) or non-growing (D) cell divided (green) or died (red) within a 24-h period (12–36 h for gen 0). Measured cumulative distributions (E) for the time to start growing (blue), time to divide (green), and time to die (red) of generation 0 cells. Distributions were used to calculate the lower bound expected probability that a dying cell had started to grow (F) assuming a molecular race between fates or an early commitment to one fate, as compared to the measured probability. For further details, please see Supplementary Methods.
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fig03: B cells decide to divide or die and are protected from the alternate fateA Flowchart depicting the scenario in which the cell fate of growing cells is determined by a race between division (green) and death (red); hypothetical division and death time distributions before and after mutual censorship are shown on the right.B Flowchart depicting the scenario in which entering the growth phase or not represents an early commitment to one fate; the independent division (green) and death (red) time distributions are shown on the right.C–F Analysis of response (growth), division, and death statistics for WT B cells. Error bars = 1/n. Measured generational probabilities that a growing (C) or non-growing (D) cell divided (green) or died (red) within a 24-h period (12–36 h for gen 0). Measured cumulative distributions (E) for the time to start growing (blue), time to divide (green), and time to die (red) of generation 0 cells. Distributions were used to calculate the lower bound expected probability that a dying cell had started to grow (F) assuming a molecular race between fates or an early commitment to one fate, as compared to the measured probability. For further details, please see Supplementary Methods.

Mentions: To further characterize the underlying cellular mechanisms, we next tested whether cell cycle and apoptosis were parallel racing processes (Fig3A), as previously suggested (Duffy et al, 2012), or whether the growth phase was indicative of a prior decision to assume the division fate instead of the death fate (Fig3B). For each generation, we counted the fraction of ‘growers’ that divided and died within a 24-h period: 12–36 h in generation 0 or 0–24 h in generations 1+ (Fig3C), as well as the fraction of ‘non-growers’ that divided and died within the same periods for each generation (Fig3D). Our results indicate that virtually all ‘growers’ in the first four generations divided, supporting the notion of an early decision that predisposes B cells to a particular fate (Fig3B). Interestingly, following the first generation, there was a significant fraction of cells that divided that had been classified as ‘non-growers’; however, such poor growth almost always occurred in the last division (Supplementary Fig S2). To further test this important distinction, we noted the time point at which growth starts (Tgro), the time to division (Tdiv), and time to death (Tdie) of progenitor cells and calculated the expected lower-bound probability that a dying cell would have grown, provided a ‘molecular race’ or ‘decision’ model (Fig3E and F). Our analysis revealed that even under relatively relaxed assumptions, the data are inconsistent with both processes occurring simultaneously in cells (i.e., race). A decision model, which commits cells to either fate, is more consistent with the observed behavior. In other words, because time to death is typically earlier than time to division (Fig3E), and because time to start growing, Tgro, is typically much earlier than Tdiv or Tdie, our analysis predicts most cells would grow prior to death if the two processes were indeed running in parallel as implied by the ‘race’ model.


A multi-scale approach reveals that NF-κB cRel enforces a B-cell decision to divide.

Shokhirev MN, Almaden J, Davis-Turak J, Birnbaum HA, Russell TM, Vargas JA, Hoffmann A - Mol. Syst. Biol. (2015)

B cells decide to divide or die and are protected from the alternate fateA Flowchart depicting the scenario in which the cell fate of growing cells is determined by a race between division (green) and death (red); hypothetical division and death time distributions before and after mutual censorship are shown on the right.B Flowchart depicting the scenario in which entering the growth phase or not represents an early commitment to one fate; the independent division (green) and death (red) time distributions are shown on the right.C–F Analysis of response (growth), division, and death statistics for WT B cells. Error bars = 1/n. Measured generational probabilities that a growing (C) or non-growing (D) cell divided (green) or died (red) within a 24-h period (12–36 h for gen 0). Measured cumulative distributions (E) for the time to start growing (blue), time to divide (green), and time to die (red) of generation 0 cells. Distributions were used to calculate the lower bound expected probability that a dying cell had started to grow (F) assuming a molecular race between fates or an early commitment to one fate, as compared to the measured probability. For further details, please see Supplementary Methods.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4358656&req=5

fig03: B cells decide to divide or die and are protected from the alternate fateA Flowchart depicting the scenario in which the cell fate of growing cells is determined by a race between division (green) and death (red); hypothetical division and death time distributions before and after mutual censorship are shown on the right.B Flowchart depicting the scenario in which entering the growth phase or not represents an early commitment to one fate; the independent division (green) and death (red) time distributions are shown on the right.C–F Analysis of response (growth), division, and death statistics for WT B cells. Error bars = 1/n. Measured generational probabilities that a growing (C) or non-growing (D) cell divided (green) or died (red) within a 24-h period (12–36 h for gen 0). Measured cumulative distributions (E) for the time to start growing (blue), time to divide (green), and time to die (red) of generation 0 cells. Distributions were used to calculate the lower bound expected probability that a dying cell had started to grow (F) assuming a molecular race between fates or an early commitment to one fate, as compared to the measured probability. For further details, please see Supplementary Methods.
Mentions: To further characterize the underlying cellular mechanisms, we next tested whether cell cycle and apoptosis were parallel racing processes (Fig3A), as previously suggested (Duffy et al, 2012), or whether the growth phase was indicative of a prior decision to assume the division fate instead of the death fate (Fig3B). For each generation, we counted the fraction of ‘growers’ that divided and died within a 24-h period: 12–36 h in generation 0 or 0–24 h in generations 1+ (Fig3C), as well as the fraction of ‘non-growers’ that divided and died within the same periods for each generation (Fig3D). Our results indicate that virtually all ‘growers’ in the first four generations divided, supporting the notion of an early decision that predisposes B cells to a particular fate (Fig3B). Interestingly, following the first generation, there was a significant fraction of cells that divided that had been classified as ‘non-growers’; however, such poor growth almost always occurred in the last division (Supplementary Fig S2). To further test this important distinction, we noted the time point at which growth starts (Tgro), the time to division (Tdiv), and time to death (Tdie) of progenitor cells and calculated the expected lower-bound probability that a dying cell would have grown, provided a ‘molecular race’ or ‘decision’ model (Fig3E and F). Our analysis revealed that even under relatively relaxed assumptions, the data are inconsistent with both processes occurring simultaneously in cells (i.e., race). A decision model, which commits cells to either fate, is more consistent with the observed behavior. In other words, because time to death is typically earlier than time to division (Fig3E), and because time to start growing, Tgro, is typically much earlier than Tdiv or Tdie, our analysis predicts most cells would grow prior to death if the two processes were indeed running in parallel as implied by the ‘race’ model.

Bottom Line: B-lymphocyte population dynamics, which are predictive of immune response and vaccine effectiveness, are determined by individual cells undergoing division or death seemingly stochastically.Combining modeling and experimentation, we found that NF-κB cRel enforces the execution of a cellular decision between mutually exclusive fates by promoting survival in growing cells.We show that a multi-scale modeling approach allows for the prediction of dynamic organ-level physiology in terms of intra-cellular molecular networks.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, Signaling Systems Laboratory, UCSD, La Jolla, CA, USA San Diego Center for Systems Biology, UCSD, La Jolla, CA, USA Bioinformatics and Systems Biology Graduate Program, UCSD, La Jolla, CA, USA.

No MeSH data available.