The transcripts of a gastrula-premarked enhancer prime posterior tissue development through cross-talk with morphogen effector

The regulatory mechanisms governing cell fate determination, particularly lineage diversification during mammalian embryonic development, remain poorly understood with in-depth regulatory paradigms yet to be fully elucidated. Here, leveraging the epigenetic landscape of mouse gastrula, we identified p-Enh, a pre-marked enhancer in primitive streak region, as pivotal regulator for posterior tissue development in mouse embryos. Morphological and single-cell transcriptomic analyses confirmed embryonic lethality phenotype with disrupted posterior tissue development trajectories in p-Enh-KO embryos. Molecularly, apart from regulating the neighboring coding-gene Cdx2 in cis , our findings suggest that p-Enh also modulate the global transcriptome and epigenomic landscape, which might through the transient production of eRNA in trans . Further investigation revealed p-Enh participate in the regulatory cascades of TGF-β signaling. Chemical modulation of TGF-β signaling can largely rescue the posterior development deficiency in in vitro gastruloids through a Cdx2 -independent mechanism. Thus, we propose a potential model in which the broadly distributed p-Enh transcripts within the nucleus could serve as essential cross-modular coordinators, priming the posterior development of mouse embryo.