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

Abstract

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, we found that p-Enh can also modulate the global transcriptome and epigenomic landscape through the transient production of chromatin-binding eRNA in trans. Further investigation revealed p-Enh-eRNA participate in the regulatory cascades of TGF-β signaling by colocalizing with TFs such as SMAD4. Chemical modulation of TGF-β signaling or over-expression of nuclei-resident eRNAs can morphologically rescue the posterior development in in vitro gastruloids. Thus, we propose that the broadly distributed p-Enh transcripts within the nucleus serve as essential coordinators to prime the posterior development of mouse embryo.