Genome-wide CRISPR screen identifies Menin and SUZ12 as regulators of human developmental timing [CUT&RUN]

Embryonic development follows a sequence of events that is broadly conserved across species, yet the pace of development is highly variable. Compared to most other species, humans exhibit a slower pace that is largely recapitulated in in vitro stem cell models, suggesting a cell-intrinsic clock that tracks time. Using the directed differentiation of human embryonic stem cells (hESCs) into neuroectoderm as a proxy for developmental timing, we performed a whole-genome CRISPR-Cas9 screen and found that epigenetic factors MEN1 and SUZ12 modulate the speed of hESC neural differentiation. Genetic and pharmacological loss-of-function of MEN1 or SUZ12 accelerates the acquisition of neural fate by altering the balance of activating H3K4me3 and repressive H3K27me3 chromatin modifications at bivalent promoters and thereby priming a faster activation of developmental genes upon differentiation. The acceleration effect is also observed in definitive endoderm, cardiomyocyte, and neuronal differentiations. These results indicate that chromatin bivalency acts a general driver of human-specific timing across all major germ layers and developmental stages. Furthermore, our study uncovers a novel functional cooperation between MEN1 and SUZ12 as a key mechanism for the temporal regulation of developmental programs.