Preprints.org · Oct 22, 2026

Recurrent Gene-Level Responses Beneath Divergent Alternative Polyadenylation in Human and Mouse Reprogramming

By Li S, Wang Z, Hu Y et al.

Alternative polyadenylation (APA) remodels transcript 3′ ends during somatic cell reprogramming. Established induced pluripotent stem cells show 3′ untranslated region (3′ UTR) shortening relative to their source cells. Whether this reflects a global proximal shift conserved across reprogramming routes is unclear. Here, we compared polyadenylation site usage between cell states in 551,201 cells from seven human and mouse single-cell reprogramming studies. Relative to sampled source cells, pluripotent cells showed a distal or near-zero global shift in human and a proximal shift in mouse. Beneath this divergence, gene-level responses in both directions recurred across studies and induction methods within each species beyond measurement-matched expectations. The global directions therefore reflected different proportions of the same response types, with more genes shifting proximally in mouse. Despite weak genome-wide correspondence between species, more orthologs than expected shared a proximal shift in pluripotent relative to mesenchymal cells from the same libraries. This shared response, mainly tandem 3′ UTR shortening, was not shown to be specific to pluripotency acquisition. Our results suggest that APA remodeling during pluripotency acquisition proceeds through gene-specific responses, some shared between species, rather than a global proximal shift conserved across the sampled routes.

doi.org/10.20944/preprints202610.2236.v1Open accessMechanisms