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Elucidating multi-input processing 3-node gene regulatory network topologies

by Juan Camilo Arboleda-Rivera, Gloria Machado-Rodríguez, Boris A. Rodríguez, Jayson Gutiérrez


In a recently published work led by Jayson Gutierrez, a postdoctoral researcher at the Flanders Marine Institute (VLIZ), a systems biology-inspired modeling approach was employed to probe the space of small gene regulatory circuit designs capable of converting a signaling molecule gradient along with a virtual developing embryo into a stereotyped spatial expression pattern..


Graphical abstract of the research
Graphical abstract of the research

Almost any conceivable biological trait emerges from the interaction of different types of molecules, which are directly or indirectly linked to the activity of a set of genes encoded in the genome of an organism. Such gene activity is critically controlled at the transcriptional level by regulatory circuits. For instance, cellular differentiation and tissue development during embryogenesis is a complex spatial-temporal patterning process tightly controlled by gene regulatory circuits.



"Thanks to the massive computational power available through the different VSC clusters, we were able to obtain meaningful results in a short period of time." -Jayson Gutierrez , Postdoctoral Researcher at VLIZ

In this work, we developed a computational model, formulated as a system of ordinary differential equations, of a virtual tissue in a developing embryo mimicking an early developmental stage of the fruit fly (Drosophila). Based on this, we simulated small gene regulatory circuits composed of 3 transcription factors, which have the ability to sense a signaling molecule (referred to as morphogen in developmental biology) forming a gradient along with an 1D array of cells. Through extensive numerical experiments, conducted via a sampling method inspired by the popular Markov chain Monte Carlo (MCMC) algorithm, we were able to identify a few thousand gene circuit designs (i.e. connectivity patterns among transcription factors) capable of converting the signaling molecule gradient into a striped gene expression pattern, a phenotype that has been recurrently observed in nature.


Compared to previous computational studies, in this work, we uncovered a list of novel gene circuit designs that are worth inquiring through synthetic biology methodologies, which might shed light on the fundamental relationship between genetically-encoded regulatory logic and observable phenotypes, under controlled experimental settings.

The insights obtained in this work derived from computer-intensive tasks involving the numerical integration of millions of gene regulatory circuit models. Thanks to the massive computational power available through the different VSC clusters, we were able to obtain meaningful results in a short period of time.


Acknowledgments

The computational resources (Stevin Supercomputer Infrastructure) and services used in this work were provided by the VSC (Flemish Supercomputer Center), funded by Ghent University, FWO and the Flemish Government–department EWI. All authors acknowledge the Colombian youth for their defense of a better country.


Read the full research article on the PLOS publishing here.


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