Multiple defects in mouse pseudo-embryos lacking all Hox function [ATAC-seq]
Mammals have four genomic copies of an ancestral Hox cluster, with a total of 39 genes. While gene inactivation approaches and full cluster deletions have revealed their critical functions during early development, the effect of removing all Hox function in the embryo has remained elusive due to both biological and technological challenges. We have used gastruloids, an embryo model where Hox genes are properly activated in time and space, to assess the effect of removing all four clusters together. We report that gastruloids lacking Hox function can still elongate and reach a general shape resembling their control counterparts, with a well-established AP polarity. However, unlike controls, they fail to produce any endoderm and are unable to properly segment their presomitic mesoderm into persistent somite-like structures when cultivated into permissive conditions. Instead, they produce a type of mesoderm with a more anterior identity, which aborts segmentation early on. Multiomics analysis revealed range of modifications in chromatin accessibility in the absence of any HOX proteins, involving in particular their PBX and MEIS co-factors. We conclude that, similar to Drosophila, mammalian HOX proteins are necessary to posteriorize an existing 'ground-state' structure by strongly interacting with PBX and MEIS cofactors, either to form instructive complexes, or to sequester the later factors to prevent their actions. In this later view, mammalian HOX proteins may be considered as a successive series of repressors, as proposed by Ed Lewis in 1978. Overall design: ATAC-seq of wt and Hox-/- mES cells cultured under standard conditions.