Cadherins modulate the self-organizing potential of gastruloids (ATAC-seq)

Gastruloids have recently emerged as an efficient four-dimensional model for studying some aspects of post-implantation embryonic patterning. Their ability to undergo gastrulation-like processes leading to the self-organization into highly reproducible biological objects, has opened new avenues to investigate early embryonic patterning. Here, we sought to uncover the molecular and cellular mechanism underlying this remarkable property. We report that self-organization competence is associated with a cell-specific coordination of a Cadherin switch. We find that N-Cadherin hinders gastruloids morphogenetic competence, for its inactivation leads to the formation of trunk-like structures without relying on the otherwise requested extra-cellular matrix analogues such as Matrigel. In contrast, the repression of E-Cadherin by Snai1 is critical for self-organization: Snai1 establishes a cell-specific repressive pace by triggering the repression of a pluripotency-associated transcription program and its chromatin landscape, thus allowing a proper transition from E- to N-Cadherin to occur. Altogether, this work establishes a molecular mechanism that integrates the exit from pluripotency and the pace of cell differentiation, leading to the observed self-organizing potential of gastruloids.