Regulatory changes associated with the head to trunk developmental transition

Abstract

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.