Robust inference of the context specific structure and temporal dynamics of gene regulatory network

During early vertebrate development, signals from a special region of the embryo, the organizer, can re-direct the fate of non-neural ectoderm cells to form a complete, patterned nervous system. This is called neural induction and has generally been imagined as a single signaling event, causing a switch of fate. Here we undertake a comprehensive analysis, in very fine time-course, of the events following exposure of ectoderm to the organizer. Using transcriptomics and epigenomics we generate a Gene Regulatory Network comprising 175 transcriptional regulators and 5,614 predicted interactions between them, with fine temporal dynamics from initial exposure to the signals to expression of mature neural plate markers. Using in situ hybridization, single-cell RNA-sequencing and reporter assays we show that neural induction by a grafted organizer mimics normal neural plate development. The study is accompanied by a comprehensive resource including information about conservation of the predicted enhancers in different vertebrate systems.

Download Full-text

The biological, biographical, and biospheric dimensions of puberty onset: Using Bio3Science to frame transdisciplinary health research on puberty

10.35831/sor/erh/rc022020 ◽

2020 ◽

Author(s):

Rebecca Croog ◽

Alexis Saenz Montoya ◽

Carlee M. Cunningham ◽

Rob J. Kulathinal ◽

Allison Hayes-Conroy

Keyword(s):

Gene Regulatory Network ◽

Health Research ◽

Regulatory Network ◽

Life Experience ◽

Human Life ◽

Health Science ◽

Three Dimensions ◽

Gene Regulatory ◽

Science Framework ◽

Context Specific

Introduction: This paper uses the case of puberty to characterize a new health science framework called Bio3Science and to provide an example of how trending research on biosocial mechanisms can be put to use to bridge siloed disciplines as well as the translational gap. Examined as an intricate, open-ended problem of scientific understanding, puberty offers a window to examine how three dimensions of human life – biology, biography, and biosphere – can be understood to shape human health and disease. Methods: Using the Bio3Science framework, a biosocial model of puberty was developed and critiqued by an interdisciplinary group of health science and social science researchers in a design studio setting. Results: The design and critique process resulted in a model and new conceptual framework that depicts puberty as a highly variable life experience that integrates multiple dense interactions and context-specific responses; within this model, the gene regulatory network (GRN) transformed from a biological to a biosocial mechanism, with conceptual and concrete applications. Conclusions: By providing a new, generalizable framework for understanding the integration of biology, biography, and biosphere in health research, opportunities emerge for more interdisciplinary work puberty, but also and more broadly, for more collaborative, inter-epistemological health research through the Bio3Science framework. Keywords: Bio3Science, puberty, biosocial, gene regulatory network, normality

Download Full-text

Temporal dynamics of a CSF1R signaling gene regulatory network involved in epilepsy

PLoS Computational Biology ◽

10.1371/journal.pcbi.1008854 ◽

2021 ◽

Vol 17 (4) ◽

pp. e1008854

Author(s):

Claude Gérard ◽

Laurane De Mot ◽

Sabine Cordi ◽

Jonathan van Eyll ◽

Frédéric P. Lemaigre

Keyword(s):

Gene Regulatory Network ◽

Regulatory Network ◽

Therapeutic Response ◽

Temporal Dynamics ◽

Therapeutic Benefit ◽

Marker Genes ◽

Mrna Levels ◽

Cell Heterogeneity ◽

Gene Regulatory ◽

Stimulating Factor

Colony Stimulating Factor 1 Receptor (CSF1R) is a potential target for anti-epileptic drugs. However, inhibition of CSF1R is not well tolerated by patients, thereby prompting the need for alternative targets. To develop a framework for identification of such alternatives, we here develop a mathematical model of a pro-inflammatory gene regulatory network (GRN) involved in epilepsy and centered around CSF1R. This GRN comprises validated transcriptional and post-transcriptional regulations involving STAT1, STAT3, NFκB, IL6R, CSF3R, IRF8, PU1, C/EBPα, TNFR1, CSF1 and CSF1R. The model was calibrated on mRNA levels of all GRN components in lipopolysaccharide (LPS)-treated mouse microglial BV-2 cells, and allowed to predict that STAT1 and STAT3 have the strongest impact on the expression of the other GRN components. Microglial BV-2 cells were selected because, the modules from which the GRN was deduced are enriched for microglial marker genes. The function of STAT1 and STAT3 in the GRN was experimentally validated in BV-2 cells. Further, in silico analysis of the GRN dynamics predicted that a pro-inflammatory stimulus can induce irreversible bistability whereby the expression level of GRN components occurs as two distinct states. The irreversibility of the switch may enforce the need for chronic inhibition of the CSF1R GRN in order to achieve therapeutic benefit. The cell-to-cell heterogeneity driven by the bistability may cause variable therapeutic response. In conclusion, our modeling approach uncovered a GRN controlling CSF1R that is predominantly regulated by STAT1 and STAT3. Irreversible inflammation-induced bistability and cell-to-cell heterogeneity of the GRN provide a theoretical foundation to the need for chronic GRN control and the limited potential for disease modification via inhibition of CSF1R.

Download Full-text