Regulatory changes associated with the head to trunk developmental transition

Abstract

Background 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 indicate that head and trunk development are significantly different, suggesting that the transition into the trunk formation stage involves major changes in regulatory gene networks. Results We explored those regulatory changes by generating differential interaction networks 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 several signaling pathways, ubiquitination machinery, ion dynamics and metabolic processes involving lipids that could contribute to the functional switch in the progenitor region of the embryo. We further explored the functional impact of changes observed in Wnt signaling associated processes, revealing a switch in the functional relevance of Wnt molecule palmitoleoylation, essential during gastrulation but becoming differentially required for the control of axial extension and progenitor differentiation processes during trunk formation. We also found substantial changes in chromatin accessibility at the two developmental stages, mostly mapping to intergenic regions and presenting differential footprinting profiles to several key transcription factors, indicating a significant switch in the regulatory elements controlling head or trunk development. Those chromatin changes are largely independent of retinoic acid, despite the key role of this factor in the transition to trunk development. We also tested the functional relevance of potential enhancers identified in the accessibility assays that reproduced the expression profiles of genes involved in the transition. 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. Conclusions This work provides a global view of the regulatory changes controlling the switch into the axial extension phase of vertebrate embryonic development. It also revealed mechanisms by which the cellular context influences the activity of regulatory factors, channeling them to implement one of several possible biological outputs.

A dual enhancer-silencer element ensures transientCdx2expression during posterior body formation

“…In addition, P2 extends the expression window in SC progenitors, yet, Cdx2 is eventually extinguished in these cells (Fig3F-I). The presence of additional, potentially long-range CREs likely explains this effect, and might also buffer fluctuations of extrinsic signalling as observed in the zebrafish neural plate border for Zic3 expression 66 and more recently in mouse embryos 64–65 .…”

“…Our results confirm that individual CREs perform indispensable roles since single CRE deletions are sufficient to perturb the expression window and cannot be compensated for by the presence of alternative, and accessible, CREs (Fig1F,I,L; Fig2F-I; Fig3D-I). The requirement for several, functionally-distinct CREs may ensure robustness in gene expression 62–64 . Consistent with this view, removal of the 5’ or P2 region within the intronic CRE has a clear but limited effect on Cdx2 expression, potentially due to the presence of additional CREs that are yet to be resolved.…”

Tgfbr1 controls developmental plasticity between the hindlimb and external genitalia by remodeling their regulatory landscape

“…While this is a continuous process, it involves two transitions entailing major changes in gene regulatory mechanisms. The first transition results in the switch from a head to a trunk developmental program 1 , marking the start of axial extension and the layout of the primordia for most of the organ systems involved in vital and reproductive functions. The second transition organizes the end of trunk structures and activates the tail developmental program 2 .…”