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Boolean modelling reveals new regulatory connections between transcription factors orchestrating the development of the ventral spinal cord.

Lovrics A, Gao Y, Juhász B, Bock I, Byrne HM, Dinnyés A, Kovács KA - PLoS ONE (2014)

Bottom Line: Such comparison highlighted the need to include additional regulatory connections in order to obtain the fixed point attractors of the model associated with the five known progenitor cell types located in the ventral spinal cord.Our results provide evidence for the existence of an as yet undescribed inhibitory connection which could potentially have significance beyond the ventral spinal cord.The work presented in this paper demonstrates the strength of Boolean modelling for identifying gene regulatory networks.

View Article: PubMed Central - PubMed

Affiliation: Biotalentum Ltd., Gödöllö, Hungary.

ABSTRACT
We have assembled a network of cell-fate determining transcription factors that play a key role in the specification of the ventral neuronal subtypes of the spinal cord on the basis of published transcriptional interactions. Asynchronous Boolean modelling of the network was used to compare simulation results with reported experimental observations. Such comparison highlighted the need to include additional regulatory connections in order to obtain the fixed point attractors of the model associated with the five known progenitor cell types located in the ventral spinal cord. The revised gene regulatory network reproduced previously observed cell state switches between progenitor cells observed in knock-out animal models or in experiments where the transcription factors were overexpressed. Furthermore the network predicted the inhibition of Irx3 by Nkx2.2 and this prediction was tested experimentally. Our results provide evidence for the existence of an as yet undescribed inhibitory connection which could potentially have significance beyond the ventral spinal cord. The work presented in this paper demonstrates the strength of Boolean modelling for identifying gene regulatory networks.

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Gene regulatory networks.(A) GRN of ventralization assembled from published experimental data. TFs are denoted by ellipses. Transcriptional inhibitions between TFs and target genes are denoted by blunted arrowheads. Associations depicted by continuous lines were demonstrated experimentally; associations denoted by dotted lines were tested with Boolean simulations. (B) Minimal GRNs obtained from Boolean simulations. Inhibition represented by continuous lines were experimentally verified, additional dashed lines represent connections present in the minimal matching GRNs. The line between Nkx2.2 and Dbx2 contains a circle at both ends representing that the direction of inhibition is not defined in the minimal GRNs.
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pone-0111430-g002: Gene regulatory networks.(A) GRN of ventralization assembled from published experimental data. TFs are denoted by ellipses. Transcriptional inhibitions between TFs and target genes are denoted by blunted arrowheads. Associations depicted by continuous lines were demonstrated experimentally; associations denoted by dotted lines were tested with Boolean simulations. (B) Minimal GRNs obtained from Boolean simulations. Inhibition represented by continuous lines were experimentally verified, additional dashed lines represent connections present in the minimal matching GRNs. The line between Nkx2.2 and Dbx2 contains a circle at both ends representing that the direction of inhibition is not defined in the minimal GRNs.

Mentions: (A) Neural progenitor cells along the dorsal-ventral axis of the ventral spinal cord and (B) the corresponding TFs. Figure 2A,B from [3] modified, with permission. (C) Binary representation of TF expression (present or absent) in each progenitor cell type in the order (Nkx2.2,Nkx6.1,Olig2,Pax6,Irx3,Dbx2,Nkx6.2,Dbx1).


Boolean modelling reveals new regulatory connections between transcription factors orchestrating the development of the ventral spinal cord.

Lovrics A, Gao Y, Juhász B, Bock I, Byrne HM, Dinnyés A, Kovács KA - PLoS ONE (2014)

Gene regulatory networks.(A) GRN of ventralization assembled from published experimental data. TFs are denoted by ellipses. Transcriptional inhibitions between TFs and target genes are denoted by blunted arrowheads. Associations depicted by continuous lines were demonstrated experimentally; associations denoted by dotted lines were tested with Boolean simulations. (B) Minimal GRNs obtained from Boolean simulations. Inhibition represented by continuous lines were experimentally verified, additional dashed lines represent connections present in the minimal matching GRNs. The line between Nkx2.2 and Dbx2 contains a circle at both ends representing that the direction of inhibition is not defined in the minimal GRNs.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4232242&req=5

pone-0111430-g002: Gene regulatory networks.(A) GRN of ventralization assembled from published experimental data. TFs are denoted by ellipses. Transcriptional inhibitions between TFs and target genes are denoted by blunted arrowheads. Associations depicted by continuous lines were demonstrated experimentally; associations denoted by dotted lines were tested with Boolean simulations. (B) Minimal GRNs obtained from Boolean simulations. Inhibition represented by continuous lines were experimentally verified, additional dashed lines represent connections present in the minimal matching GRNs. The line between Nkx2.2 and Dbx2 contains a circle at both ends representing that the direction of inhibition is not defined in the minimal GRNs.
Mentions: (A) Neural progenitor cells along the dorsal-ventral axis of the ventral spinal cord and (B) the corresponding TFs. Figure 2A,B from [3] modified, with permission. (C) Binary representation of TF expression (present or absent) in each progenitor cell type in the order (Nkx2.2,Nkx6.1,Olig2,Pax6,Irx3,Dbx2,Nkx6.2,Dbx1).

Bottom Line: Such comparison highlighted the need to include additional regulatory connections in order to obtain the fixed point attractors of the model associated with the five known progenitor cell types located in the ventral spinal cord.Our results provide evidence for the existence of an as yet undescribed inhibitory connection which could potentially have significance beyond the ventral spinal cord.The work presented in this paper demonstrates the strength of Boolean modelling for identifying gene regulatory networks.

View Article: PubMed Central - PubMed

Affiliation: Biotalentum Ltd., Gödöllö, Hungary.

ABSTRACT
We have assembled a network of cell-fate determining transcription factors that play a key role in the specification of the ventral neuronal subtypes of the spinal cord on the basis of published transcriptional interactions. Asynchronous Boolean modelling of the network was used to compare simulation results with reported experimental observations. Such comparison highlighted the need to include additional regulatory connections in order to obtain the fixed point attractors of the model associated with the five known progenitor cell types located in the ventral spinal cord. The revised gene regulatory network reproduced previously observed cell state switches between progenitor cells observed in knock-out animal models or in experiments where the transcription factors were overexpressed. Furthermore the network predicted the inhibition of Irx3 by Nkx2.2 and this prediction was tested experimentally. Our results provide evidence for the existence of an as yet undescribed inhibitory connection which could potentially have significance beyond the ventral spinal cord. The work presented in this paper demonstrates the strength of Boolean modelling for identifying gene regulatory networks.

Show MeSH
Related in: MedlinePlus