Cadherins modulate the self-organizing potential of gastruloids (ATAC-seq). 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. Overall design: ATAC-seq on gastruloids from WT and mutant conditions

类原肠胚（Gastruloids）近来已成为研究植入后胚胎模式建成部分环节的高效四维模型。其能够发生原肠运动样过程，进而自组织为高度可重复的生物结构体，这一特性为早期胚胎模式建成的研究开辟了全新路径。本研究旨在揭示这一卓越特性背后的分子与细胞机制。我们发现，自组织能力与钙粘蛋白转换的细胞特异性协调密切相关。研究表明，N-钙粘蛋白（N-Cadherin）会抑制类原肠胚的形态发生能力：当其失活时，无需依赖基质胶（Matrigel）这类常规所需的细胞外基质类似物，即可形成躯干样结构。与之相反，Snai1对E-钙粘蛋白（E-Cadherin）的抑制对于自组织过程至关重要：Snai1通过触发多能性相关转录程序及其染色质景观的抑制，建立起细胞特异性的抑制节奏，从而确保E-钙粘蛋白向N-钙粘蛋白的正常转换得以完成。综上，本研究确立了一套整合多能性退出与细胞分化节奏的分子机制，该机制可解释类原肠胚所展现的自组织潜能。实验整体设计：对野生型（WT）与突变体条件下的类原肠胚进行转座酶可及性测序（ATAC-seq）分析。