Stem Cell Differentiation Disperses Transcriptional Clusters via a Conserved Surface‐Condensate Trajectory

ABSTRACT Stem cells exhibit exceptionally prominent transcriptional clusters, which dissolve with progressing differentiation. Although these clusters are assigned central roles in embryonic gene regulation, their formation and loss during differentiation remain poorly understood. This study reveals that these prominent clusters disperse along a conserved trajectory in mouse embryonic stem cells, fruit fly testes, and zebrafish embryos. Imaging and lattice simulations show that these clusters form via surface condensation on H3K27ac‐marked super‐enhancer regions, which act as genomic scaffolds. Upon differentiation, partial loss of these active epigenetic marks and transcription‐driven unfolding lead to dispersal of the prominent clusters. The block copolymer‐based lattice simulations explain this process as a conserved trajectory through a three‐dimensional state space, governed by surface condensation principles that extend beyond canonical liquid–liquid phase separation. This work marks surface condensation as a biophysical mechanism for the dynamic organization of stem cell‐specific transcriptional hubs and demonstrates evolutionary conservation in several organisms. By uncovering a conserved biophysical mechanism for transcriptional organization in development, our work illustrates how polymer properties can contribute to the control of cell identity and fate.