Chromatin establishes an immature version of neuronal protocadherin selection during the naive-to-primed conversion of pluripotent stem cells

In the mammalian genome, the clustered protocadherin (cPcdh) locus is a paradigm of stochastic gene expression with the potential to generate a unique cPcdh combination in every neuron. Here, we report a chromatin-based mechanism emerging during the transition from the naive to the primed states of cell pluripotency that reduces by orders of magnitude the combinatorial potential in the human cPcdh locus. This mechanism selectively increases the frequency of stochastic selection of a small subset of cPcdh genes after neuronal differentiation in monolayers, months-old organoids, and engrafted cells in the rat spinal cord. Signs of these frequent selections can be observed in the brain throughout fetal development and disappear after birth, unless there is a condition of delayed maturation such as Down Syndrome. We therefore propose that a pattern of limited cPcdh diversity is maintained while human neurons still retain fetal-like levels of maturation.