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Pairing of competitive and topologically distinct regulatory modules enhances patterned gene expression.

Yanai I, Baugh LR, Smith JJ, Roehrig C, Shen-Orr SS, Claggett JM, Hill AA, Slonim DK, Hunter CP - Mol. Syst. Biol. (2008)

Bottom Line: Based on these results, we define and characterize two modules composed of muscle- and epidermal-specifying transcription factors that function together within a single cell lineage to robustly specify multiple cell types.The expression of these two modules, although positively regulated by a common factor, is reliably segregated among daughter cells.The coupling of asynchronous and topologically distinct modules may be a general principle of module assembly that functions to potentiate genetic switches.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.

ABSTRACT
Biological networks are inherently modular, yet little is known about how modules are assembled to enable coordinated and complex functions. We used RNAi and time series, whole-genome microarray analyses to systematically perturb and characterize components of a Caenorhabditis elegans lineage-specific transcriptional regulatory network. These data are supported by selected reporter gene analyses and comprehensive yeast one-hybrid and promoter sequence analyses. Based on these results, we define and characterize two modules composed of muscle- and epidermal-specifying transcription factors that function together within a single cell lineage to robustly specify multiple cell types. The expression of these two modules, although positively regulated by a common factor, is reliably segregated among daughter cells. Our analyses indicate that these modules repress each other, and we propose that this cross-inhibition coupled with their relative time of induction function to enhance the initial asymmetry in their expression patterns, thus leading to the observed invariant gene expression patterns and cell lineage. The coupling of asynchronous and topologically distinct modules may be a general principle of module assembly that functions to potentiate genetic switches.

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A model for the C lineage developmental regulatory network. A model for how pal-1 robustly specifies and patterns multiple cell fates. The expression and inferred regulatory interactions among C lineage TFs in only the posterior C daughter and its immediate descendants are shown, but the model is the same for the anterior C daughter. PAL-1 and TBX-8,9 initiate C blastomere development, inducing first elt-1 such that ELT-1 is present in all cells at the 4C stage. In the daughters of the anterior cell (8C stage), ELT-1 continues to be expressed and is active, inducing the second stage epidermal TFs and repressing the muscle module. In the posterior daughter cell, ELT-1 expression is not maintained and all three muscle module TFs are strongly activated, rapidly leading to a self-sustaining (inducer independent) expression state—the presented muscle module topology is one of the several self-sustaining topologies consistent with the data (see text). The TF POP-1 is asymmetrically deployed in these anterior-posterior daughters at the 4C stage, but it is unknown whether POP-1 represses muscle development in the anterior daughter cells and/or activates muscle module expression in posterior daughter cells. POP-1 and/or its regulators may also influence ELT-1 activity.
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f6: A model for the C lineage developmental regulatory network. A model for how pal-1 robustly specifies and patterns multiple cell fates. The expression and inferred regulatory interactions among C lineage TFs in only the posterior C daughter and its immediate descendants are shown, but the model is the same for the anterior C daughter. PAL-1 and TBX-8,9 initiate C blastomere development, inducing first elt-1 such that ELT-1 is present in all cells at the 4C stage. In the daughters of the anterior cell (8C stage), ELT-1 continues to be expressed and is active, inducing the second stage epidermal TFs and repressing the muscle module. In the posterior daughter cell, ELT-1 expression is not maintained and all three muscle module TFs are strongly activated, rapidly leading to a self-sustaining (inducer independent) expression state—the presented muscle module topology is one of the several self-sustaining topologies consistent with the data (see text). The TF POP-1 is asymmetrically deployed in these anterior-posterior daughters at the 4C stage, but it is unknown whether POP-1 represses muscle development in the anterior daughter cells and/or activates muscle module expression in posterior daughter cells. POP-1 and/or its regulators may also influence ELT-1 activity.

Mentions: We investigated a transcriptional regulatory network that controls the development of an embryonic cell lineage to produce muscle and epidermal cell fates. The goal was to infer the topology of the regulatory network by determining the near immediate transcriptional consequences of knocking down each constituent TF. The microarray analysis afforded a direct, unbiased, and highly parallel approach to determine the phenotype of the network at discrete time points; however, it was also limiting as the sparse temporal sampling likely missed some significant changes in gene expression. The expression data were complemented by a systematic yeast one-hybrid binding analysis of all C lineage TFs as well as computational analysis to identify likely functional cis-binding sites for these TFs. From these data, we are able to infer whether and how the expression of any gene depends on the function of any of the 13 TFs that comprise the C lineage transcriptional regulatory network. We found that two highly connected subnetworks, or modules, control specification of muscle and epidermal cell fates and that these modules repress each other, effectively competing to specify alternative cell fates (Figure 6). Here, we discuss these results and their implications in our efforts to understand how a single TF (pal-1) can specify and pattern multiple, mutually exclusive cell fates in a single-cell lineage. Future experiments will undoubtedly further refine the model and promise to yield new insight into cell fate specification.


Pairing of competitive and topologically distinct regulatory modules enhances patterned gene expression.

Yanai I, Baugh LR, Smith JJ, Roehrig C, Shen-Orr SS, Claggett JM, Hill AA, Slonim DK, Hunter CP - Mol. Syst. Biol. (2008)

A model for the C lineage developmental regulatory network. A model for how pal-1 robustly specifies and patterns multiple cell fates. The expression and inferred regulatory interactions among C lineage TFs in only the posterior C daughter and its immediate descendants are shown, but the model is the same for the anterior C daughter. PAL-1 and TBX-8,9 initiate C blastomere development, inducing first elt-1 such that ELT-1 is present in all cells at the 4C stage. In the daughters of the anterior cell (8C stage), ELT-1 continues to be expressed and is active, inducing the second stage epidermal TFs and repressing the muscle module. In the posterior daughter cell, ELT-1 expression is not maintained and all three muscle module TFs are strongly activated, rapidly leading to a self-sustaining (inducer independent) expression state—the presented muscle module topology is one of the several self-sustaining topologies consistent with the data (see text). The TF POP-1 is asymmetrically deployed in these anterior-posterior daughters at the 4C stage, but it is unknown whether POP-1 represses muscle development in the anterior daughter cells and/or activates muscle module expression in posterior daughter cells. POP-1 and/or its regulators may also influence ELT-1 activity.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2267734&req=5

f6: A model for the C lineage developmental regulatory network. A model for how pal-1 robustly specifies and patterns multiple cell fates. The expression and inferred regulatory interactions among C lineage TFs in only the posterior C daughter and its immediate descendants are shown, but the model is the same for the anterior C daughter. PAL-1 and TBX-8,9 initiate C blastomere development, inducing first elt-1 such that ELT-1 is present in all cells at the 4C stage. In the daughters of the anterior cell (8C stage), ELT-1 continues to be expressed and is active, inducing the second stage epidermal TFs and repressing the muscle module. In the posterior daughter cell, ELT-1 expression is not maintained and all three muscle module TFs are strongly activated, rapidly leading to a self-sustaining (inducer independent) expression state—the presented muscle module topology is one of the several self-sustaining topologies consistent with the data (see text). The TF POP-1 is asymmetrically deployed in these anterior-posterior daughters at the 4C stage, but it is unknown whether POP-1 represses muscle development in the anterior daughter cells and/or activates muscle module expression in posterior daughter cells. POP-1 and/or its regulators may also influence ELT-1 activity.
Mentions: We investigated a transcriptional regulatory network that controls the development of an embryonic cell lineage to produce muscle and epidermal cell fates. The goal was to infer the topology of the regulatory network by determining the near immediate transcriptional consequences of knocking down each constituent TF. The microarray analysis afforded a direct, unbiased, and highly parallel approach to determine the phenotype of the network at discrete time points; however, it was also limiting as the sparse temporal sampling likely missed some significant changes in gene expression. The expression data were complemented by a systematic yeast one-hybrid binding analysis of all C lineage TFs as well as computational analysis to identify likely functional cis-binding sites for these TFs. From these data, we are able to infer whether and how the expression of any gene depends on the function of any of the 13 TFs that comprise the C lineage transcriptional regulatory network. We found that two highly connected subnetworks, or modules, control specification of muscle and epidermal cell fates and that these modules repress each other, effectively competing to specify alternative cell fates (Figure 6). Here, we discuss these results and their implications in our efforts to understand how a single TF (pal-1) can specify and pattern multiple, mutually exclusive cell fates in a single-cell lineage. Future experiments will undoubtedly further refine the model and promise to yield new insight into cell fate specification.

Bottom Line: Based on these results, we define and characterize two modules composed of muscle- and epidermal-specifying transcription factors that function together within a single cell lineage to robustly specify multiple cell types.The expression of these two modules, although positively regulated by a common factor, is reliably segregated among daughter cells.The coupling of asynchronous and topologically distinct modules may be a general principle of module assembly that functions to potentiate genetic switches.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.

ABSTRACT
Biological networks are inherently modular, yet little is known about how modules are assembled to enable coordinated and complex functions. We used RNAi and time series, whole-genome microarray analyses to systematically perturb and characterize components of a Caenorhabditis elegans lineage-specific transcriptional regulatory network. These data are supported by selected reporter gene analyses and comprehensive yeast one-hybrid and promoter sequence analyses. Based on these results, we define and characterize two modules composed of muscle- and epidermal-specifying transcription factors that function together within a single cell lineage to robustly specify multiple cell types. The expression of these two modules, although positively regulated by a common factor, is reliably segregated among daughter cells. Our analyses indicate that these modules repress each other, and we propose that this cross-inhibition coupled with their relative time of induction function to enhance the initial asymmetry in their expression patterns, thus leading to the observed invariant gene expression patterns and cell lineage. The coupling of asynchronous and topologically distinct modules may be a general principle of module assembly that functions to potentiate genetic switches.

Show MeSH