Transcription factor ZNF263 primes human embryonic stem cells for pluripotency dissolution and early differentiation [CUT&Tag]

Conventional human embryonic stem cells (hESCs) are capable of self-renewal and simultaneously poised for differentiation, and thus have been considered to resemble a primed pluripotent state. But the underlying regulatory mechanisms remain largely underexplored. Especially, little was known about the pivotal transcription factors (TFs) driving hESCs through the naïve-to-primed transition to prepare for differentiation. Here, we conduct a large-scale in-silico screening and identify ZNF263 as a new key TF in primed hESCs, as evidenced by its extensive binding capacity at the active and poised genes. Genetic and functional assays reveal that ZNF263 directly initiates the incipient expression of early differentiation genes and concurrently dampens the core pluripotency circuitry in hESCs, greatly tilting the balance from pluripotency maintenance to lineage priming. Importantly, ZNF263 deficiency in hESCs further led to clear defects in pluripotency dissolution and lineage commitment, suggesting it’s indispensably required for the whole process. Together, our results demonstrate a pivotal role of ZNF263 in coordinating the establishment of primed pluripotency state in hESCs and facilitating the differentiation into primary germ layer lineages, which opens a new gate for understanding the central regulatory network governing human early development.