Brattig Correia, R. | Search bioRxiv

bioRxiv2022

Regulatory changes associated with the head to trunk developmental transition

Development of vertebrate embryos is characterized by early formation of the anterior tissues followed by the sequential extension of the axis at their posterior end to build the trunk and tail structures, first by the activity of the primitive streak and then of the tail bud. Embryological, molecular and genetic data demonstrate that head and trunk development are significantly different, indicating that the transition into the trunk formation stage involves changes in regulatory gene networks, that might include the acquisition of cell competence to respond to key regulatory factors. Herein, we explored the regulatory changes involved in this developmental transition by assessing the transcriptome and chromatin accessibility profiles from the posterior epiblast region of mouse embryos at embryonic day (E)7.5 and E8.5. We observed changes in various cell processes, including signaling pathways, ubiquitination, ion dynamics and metabolic processes involving lipids that could contribute to the functional switch in the progenitor region of the embryo. Our data also led to the identification of novel mechanisms controlling the differential Wnt functional requirements during head and trunk development. Moreover, we found substantial changes in chromatin accessibility mostly mapping to intergenic regions, indicating a significant switch in the regulatory elements controlling either head or trunk development. In addition, we tested the functional relevance of potential enhancers of Wnt5a and Nr2f2, identified in the accessibility assays, that reproduced the expression profiles of the target genes. Deletion of these regions by genome editing had limited effect on the expression of those genes, suggesting the existence of redundant enhancers that guarantee robust expression patterns. Overall, this study provides new insights on the regulatory mechanisms that change during the transition from head to trunk development. Author SummaryVertebrate main body axis is generated sequentially from head to tail. The developmental processes building head and trunk structures are significantly different, and the transition between these two stages requires substantial changes in functional gene regulatory networks. Herein, we explored such changes through genome wide analyses in developing mouse embryos. We observed significant differences in several signaling pathways and in the basic cell machinery, which may interact promoting a functional switch in the differentiating progenitor cells. We also found substantial changes in the accessibility of regulatory elements controlling either head or trunk formation, which conditioned the binding activity of key developmental transcription factors. Overall, our study gives relevant insights into the mechanisms regulating the head to trunk transition that, if disrupted, can lead to embryonic developmental arrest.

developmental biology↗

bioRxiv2022

The metric backbone preserves community structure and is a primary transmission subgraph in contact networks

The structure of social networks strongly affects how different phenomena spread in human society, from the transmission of information to the propagation of contagious diseases. It is well-known that heterogeneous connectivity strongly favors spread, but a precise characterization of the redundancy present in social networks and its effect on the robustness of transmission is still lacking. This gap is addressed by the metric backbone, a weight- and connectivity-preserving subgraph that is sufficient to compute all shortest paths of weighted graphs. This subgraph is obtained via algebraically-principled axioms and does not require statistical sampling based on null-models. We show that the metric backbones of nine contact networks obtained from proximity sensors in a variety of social contexts are generally very small, 49% of the original graph for one and ranging from about 6% to 20% for the others. This reflects a surprising amount of redundancy and reveals that shortest paths on these networks are very robust to random attacks and failures. We also show that the metric backbone preserves the full distribution of shortest paths of the original contact networks--which must include the shortest inter- and intra-community distances that define any community structure--and is a primary subgraph for epidemic transmission based on pure diffusion processes. This suggests that the organization of social contact networks is based on large amounts of shortest-path redundancy which shapes epidemic spread in human populations. Thus, the metric backbone is an important subgraph with regard to epidemic spread, the robustness of social networks, and any communication dynamics that depend on complex network shortest paths. Author summaryIt is through social networks that contagious diseases spread in human populations, as best illustrated by the current pandemic and efforts to contain it. Measuring such networks from human contact data typically results in noisy and dense graphs that need to be simplified for effective analysis, without removal of their essential features. Thus, the identification of a primary subgraph that maintains the social interaction structure and likely transmission pathways is of relevance for studying epidemic spreading phenomena as well as devising intervention strategies to hinder spread. Here we propose and study the metric backbone as an optimal subgraph for sparsification of social contact networks in the study of simple spreading dynamics. We demonstrate that it is a unique, algebraically-principled network subgraph that preserves all shortest paths. We also discover that nine contact networks obtained from proximity sensors in a variety of social contexts contain large amounts of redundant interactions that can be removed with very little impact on community structure and epidemic spread. This reveals that epidemic spread on social networks is very robust to random interaction removal. However, extraction of the metric backbone subgraph reveals which interventions--strategic removal of specific social interactions--are likely to result in maximum impediment to epidemic spread.

systems biology↗