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Determining genes orchestrating cell identity and function in development and disease remains a fundamental goal of cell biology. This study establishes a genome-wide metric based on the gene-repressive tri-methylation of histone 3 lysine 27 as deposited in over 100 human cell states from representative tissues and cell lines. On its own, the tendency of broad H3K27me3 occupancy at promoters strongly enriches for genes that drive cell diversification and fates. We show that the discordance between this repressive tendency and the abundance of expressed transcripts of any somatic cell type prioritizes cell type-specific regulatory genes in health and disease. We implement this repression-based regulatory logic to identify genetic drivers of cell identity across millions of genome-wide single cell transcriptomes, diverse omics platforms, and eukaryotic cells and tissue types. Its potential for novel gene discovery is demonstrated by experimentally validated predictions of previously unknown drivers of organ differentiation in two eukaryotic species, humans and Ciona. This simple and quantifiable regulatory inference analysis provides a novel and scalable computational approach to determine drivers of cell diversification and fates of any cell type from gene output alone. ### Competing Interest Statement The authors have declared no competing interest.

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