Pulsed Feedback Defers Cellular Differentiation

Levine, Joe H.; Fontes, Michelle E.; Dworkin, Jonathan; Elowitz, Michael B.

doi:10.1371/journal.pbio.1001252

Cited by 98 publications

(132 citation statements)

References 51 publications

(63 reference statements)

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“…We note that we have no direct control of the Spo0A activity in this setup, and therefore cannot probe the input-output response of the network directly at the population level. Nevertheless, because Spo0A activity is broadly heterogeneous during starvation (16,17,21,22), correlations between activities of Spo0A and sigma factor can be examined in single cells over a wide range of values. Therefore, to determine if activation of σ F and σ E is ultrasensitive to increases in Spo0A activity, we simultaneously measured activities of Spo0A and sigma factors during starvation.…”

Section: Resultsmentioning

confidence: 99%

“…This hypothesis is motivated by the observation that an increase in Spo0A∼P is sufficient to shift the site of cell division to an asymmetrical polar site, and thereby to initiate sporulation (19,20). However, the hypothesis of a single Spo0A∼P threshold has been undermined by recent studies showing that (i) starving populations of B. subtilis exhibit broad and unimodal distributions of Spo0A activity (16,17,21) and (ii) there is significant overlap in distributions of Spo0A activity in sporulating and nonsporulating cells (22). Moreover, cells that form an asymmetrical septum but do not activate σ F and/or σ E are able to resume vegetative growth (23)(24)(25).…”

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confidence: 99%

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Ultrasensitivity of the Bacillus subtilis sporulation decision

Narula

Devi

Fujita

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Starving Bacillus subtilis cells execute a gene expression program resulting in the formation of stress-resistant spores. Sporulation master regulator, Spo0A, is activated by a phosphorelay and controls the expression of a multitude of genes, including the forespore-specific sigma factor σ F and the mother cell-specific sigma factor σ E . Identification of the system-level mechanism of the sporulation decision is hindered by a lack of direct control over Spo0A activity. This limitation can be overcome by using a synthetic system in which Spo0A activation is controlled by inducing expression of phosphorelay kinase KinA. This induction results in a switch-like increase in the number of sporulating cells at a threshold of KinA. Using a combination of mathematical modeling and single-cell microscopy, we investigate the origin and physiological significance of this ultrasensitive threshold. The results indicate that the phosphorelay is unable to achieve a sufficiently fast and ultrasensitive response via its positive feedback architecture, suggesting that the sporulation decision is made downstream. In contrast, activation of σ F in the forespore and of σ E in the mother cell compartments occurs via a cascade of coherent feed-forward loops, and thereby can produce fast and ultrasensitive responses as a result of KinA induction. Unlike σ F activation, σ E activation in the mother cell compartment only occurs above the KinA threshold, resulting in completion of sporulation. Thus, ultrasensitive σ E activation explains the KinA threshold for sporulation induction. We therefore infer that under uncertain conditions, cells initiate sporulation but postpone making the sporulation decision to average stochastic fluctuations and to achieve a robust population response.cell fate | development | differentiation | stochasticity | network I n response to nutrient deprivation, Bacillus subtilis cells undergo asymmetrical cell division and then follow a cell differentiation program resulting in formation of metabolically inert spores (1, 2) (Fig. 1A). Sporulation requires the execution of a complex gene expression program involving hundreds of "sporulation" genes (3-6). The availability of a large number of genetic mutants that differ from the WT only in their sporulation response makes B. subtilis an ideal model system to study the relationship between gene expression and cell fate specification during bacterial differentiation (7).Progression of the sporulation program is under the control of a large regulatory network (hereafter called the sporulation network). This network involves the sporulation master regulator Spo0A and five alternative sigma factors (σ H , σ F , σ E , σ K , and σ G ) that are activated in precise temporal order (8). Initiation of the sporulation program is controlled by Spo0A (4, 9). The activity and concentration of this master transcription factor are regulated by phosphorelay through both posttranslational and transcriptional interactions (10). Posttranslationally, phosphoryl groups are transferred fro...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Ultrasensitivity of the Bacillus subtilis sporulation decision

Narula

Devi

Fujita

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…In addition, the considerable delay in NmFic-mediated GyrB adenylylation may be important in vivo to ensure that the growth-retarding effect of the target modification kicks in only under certain conditions, such as starvation, when synthesis of fresh NmFic has come to a halt. Molecular timers have been found before, such as the master regulator Spo0A of Bacillus that controls, upon phosphorylation, the switch from competence to sporulation via a well-characterized genetic circuit (21,22) induced by prolonged times of nutriment starvation. Class III Fic proteins may constitute a new family of molecular timers that are, in contrast to the master regulator Spo0A of Bacillus, fully autonomous and not relying on any feedback exerted by other components or a genetic circuit.…”

Section: Discussionmentioning

confidence: 99%

Intrinsic regulation of FIC-domain AMP-transferases by oligomerization and automodification

Stanger

Burmann

Harms

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Filamentation induced by cyclic AMP (FIC)-domain enzymes catalyze adenylylation or other posttranslational modifications of target proteins to control their function. Recently, we have shown that Fic enzymes are autoinhibited by an α-helix (α inh ) that partly obstructs the active site. For the single-domain class III Fic proteins, the α inh is located at the C terminus and its deletion relieves autoinhibition. However, it has remained unclear how activation occurs naturally. Here, we show by structural, biophysical, and enzymatic analyses combined with in vivo data that the class III Fic protein NmFic from Neisseria meningitidis gets autoadenylylated in cis, thereby autonomously relieving autoinhibition and thus allowing subsequent adenylylation of its target, the DNA gyrase subunit GyrB. Furthermore, we show that NmFic activation is antagonized by tetramerization. The combination of autoadenylylation and tetramerization results in nonmonotonic concentration dependence of NmFic activity and a pronounced lag phase in the progress of target adenylylation. Bioinformatic analyses indicate that this elaborate dual-control mechanism is conserved throughout class III Fic proteins.adenylylation | AMPylation | posttranslational modification | enzyme regulation | molecular timer

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“…These studies reveal that after several rounds of division a genetic factor accumulates, reaching a threshold to initiate a cell fate change (Dugas et al, 2007;Insco et al, 2009;Levine et al, 2012). Alternatively, one could imagine dilution of a factor wherein progressive loss of this factor extends cell cycle progression leading to dormancy during homeostatic aging.…”

Section: A Mechanism Of Cell Division Counting May Underlie Age-relatmentioning

confidence: 99%

Hematopoietic stem cells count and remember self-renewal divisions

Bernitz¹,

MacArthur

Sieburg

et al. 2016

Experimental Hematology

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SummaryThe ability of cells to count and remember their divisions could underlie many alterations that occur during development, aging, and disease. We tracked the cumulative divisional history of slow-cycling hematopoietic stem cells (HSCs) throughout adult life. This revealed a fraction of rarely dividing HSCs that contained all the long-term HSC (LT-HSC) activity within the aging HSC compartment. During adult life, this population asynchronously completes four traceable symmetric self-renewal divisions to expand its size before entering a state of dormancy. We show that the mechanism of expansion involves progressively lengthening periods between cell divisions, with long-term regenerative potential lost upon a fifth division. Our data also show that age-related phenotypic changes within the HSC compartment are divisional history dependent. These results suggest that HSCs accumulate discrete memory stages over their divisional history and provide evidence for the role of cellular memory in HSC aging. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. HHS Public Access Graphical AbstractHSCs count and remember the number of times they have divided to limit the number of cell divisions, a mechanism that may underlie HSC aging.

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Pulsed Feedback Defers Cellular Differentiation

Abstract: In response to sudden environmental stress, B. subtilis cells can defer sporulation for multiple cell cycles using a pulsed positive feedback loop.

Cited by 98 publications

References 51 publications

Ultrasensitivity of the Bacillus subtilis sporulation decision

Ultrasensitivity of the Bacillus subtilis sporulation decision

Intrinsic regulation of FIC-domain AMP-transferases by oligomerization and automodification

Hematopoietic stem cells count and remember self-renewal divisions

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