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Divergent co-option of Bcl11 paralogs controls progression through cell fate conversions [scRNA-seq]

ABSTRACT: Cell fate conversions rely on pioneer transcription factors (TF) that remodel cellular identity, yet how resident somatic TFs are repurposed during these processes remains poorly understood. Here, we identify the paralogous TFs Bcl11a and Bcl11b as antagonistic regulators of pluripotent reprogramming, neuronal transdifferentiation and oncogenic transformation in vitro. Bcl11a and Bcl11b segregate into cellular intermediates that are respectively permissive or refractory to cell fate conversion (CFC). Functional perturbation demonstrates that Bcl11a promotes, whereas Bcl11b restricts, progression through cell fate transitions. Bcl11a facilitates efficient exit from intermediate states by promoting loss of fibroblast identity, limiting senescence, supporting epithelial transition during reprogramming and enabling late neuronal program activation during transdifferentiation. Mechanistically, we show that, unlike Bcl11b, Bcl11a is extensively repurposed by Oct4 during reprogramming. Oct4 redistributes Bcl11a away from fibroblast enhancers and transiently recruits it to regulatory elements controlling the ubiquitin ligase Pja1, thereby restraining Smad signalling, promoting mesenchymal-to-epithelial transition and preventing senescence. Together, our findings reveal that closely related somatic TFs can be differentially co-opted by pioneer TFs to acquire opposing functions during CFC, establishing TF versatility as a general mechanism regulating cellular plasticity.

ORGANISM(S): Mus musculus

PROVIDER: GSE283581 | GEO | 2026/09/17

REPOSITORIES: GEO

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