Ezh2 Control of Bivalent Genes Fine-Tunes Developmental Competence During Retinogenesis

Polycomb group proteins play central roles in developmental gene regulation, yet how their genome-wide chromatin occupancy relates to transcriptional control in the developing retina remains incompletely defined. Here, we characterize the genomic distribution of EZH2, the catalytic subunit of the Polycomb repressive complex 2 (PRC2), and examine its relationship to chromatin state and gene expression in the developing mouse retina. EZH2 is enriched at promoters and regulatory regions marked by H3K27me3, consistent with its role in transcriptional repression. Integrated analysis of EZH2 binding, H3K27me3 deposition, and transcriptomic changes upon Ezh2 loss revealed that bivalent genes marked by Ezh2 are particularly susceptible to derepression, highlighting a poised yet transcriptionally restrained state maintained by EZH2 in RPCs. We provide evidence for coordinated activity between retinal progenitor cell transcription factors and PRC2 in fine-tuning developmental gene-expression programs and controlling retinal cell-fate decisions. Notably, PRC2 restrains a subset of non-neuronal developmental regulators by repressing transcriptionally competent enhancer–promoter circuitries already primed by lineage-specific transcription factors. Loss of EZH2 unlocks these poised regulatory elements, driving aberrant gene activation and revealing how PRC2 prevents activation of non-retinal developmental gene programs. Collectively, these results highlight EZH2’s critical role in controlling developmental gene expression and preserving lineage fidelity during retinogenesis.