Zfp281 orchestrates interconversion of pluripotent states by engaging Ehmt1 and Zic2

Abstract

Developmental cell fate specification is a unidirectional process that can be reverted in response to injury or experimental reprogramming. Whether differentiation and de‐differentiation trajectories intersect mechanistically is unclear. Here, we performed comparative screening in lineage‐related mouse naïve embryonic stem cells (ESCs) and primed epiblast stem cells (EpiSCs), and identified the constitutively expressed zinc finger transcription factor (TF) Zfp281 as a bidirectional regulator of cell state interconversion. We showed that subtle chromatin binding changes in differentiated cells translate into activation of the histone H3 lysine 9 (H3K9) methyltransferase Ehmt1 and stabilization of the zinc finger TF Zic2 at enhancers and promoters. Genetic gain‐of‐function and loss‐of‐function experiments confirmed a critical role of Ehmt1 and Zic2 downstream of Zfp281 both in driving exit from the ESC state and in restricting reprogramming of EpiSCs. Our study reveals that cell type‐invariant chromatin association of Zfp281 provides an interaction platform for remodeling the cis‐regulatory network underlying cellular plasticity.