Reversible epiblast regionalisation determines differentiation potential of human PSCs [CUT&Tag]

Although the epiblast in the embryo has the capacity to generate all tissues of the body, its in vitro counterparts often exhibit differentiation biases, posing significant challenges for both basic research and translational applications involving pluripotent stem cells (PSCs). The origins of these biases remain incompletely understood. In this study, we identify regional epiblast identity as the hallmark of differentiation competency through fluctuations in repressive and activating histone posttranslational modifications. We present a novel approach to overcome this bias using a chemical chromatin restoration (CHR) treatment. This method restores transcriptional programs, chromatin accessibility, histone modification profiles, and differentiation potential, effectively recapitulating the competent anterior epiblast-like state. Furthermore, we propose that a high bivalency state is a defining feature of the anterior human epiblast and is a characteristic of unbiased PSCs. We suggest that fluctuations in histone modification marks drive epiblast regionalization, ultimately shaping cellular responses to differentiation cues.