The Architecture of Cell Fate Determination: The ARC Model

Abstract

Cell fate decisions in renewing tissues require coordination among chromatin modification, organelle partitioning, and cell death machinery. This manuscript proposes the ARC (Asymmetry–Remodeling–Commitment) model, in which DDR-associated enzymes function as architects of the chromatin transitions that specify cell fate through write/erase chemistry at specific genomic addresses, with partition-mediated organelle inheritance coupling the nuclear program to the cytoplasmic outcome. The model organizes cell fate progression into three molecular states orthogonal to the cell cycle: Asymmetry (initiating partition that creates molecularly divergent daughters), Remodeling (buffered chromatin changes at commitment-relevant addresses), and Commitment (irreversible resolution through compound sequence, epigenetic, and structural changes). The same enzymatic machinery that executes regulated cell death operates at sub-lethal intensity during terminal differentiation, with the partition-inherited organelle configuration determining which death-associated chemistry each daughter engages. Cancer is interpreted as a disruption of the regulatory coordination that governs these transitions, producing cells that retain functional execution machinery but have lost the partition-dependent programs that would direct it toward coherent outcomes. Computational analysis across nine TCGA cancer types, seven CPTAC proteomic cohorts, single-cell data from hematopoietic differentiation, and a mouse cross-species atlas provides evidence that the coordination the model describes is present in normal tissue, varies across tissues in ways that track regenerative capacity, changes progressively along differentiation trajectories, and dissolves selectively in cancer. Pairwise coupling between regulatory coordination components weakens systematically in tumor tissue while structurally obligate execution partnerships are preserved — a selective dissolution reproduced at protein level, at single-cell resolution, and across species. Five lineage-specific failure modes are identified and tested against representative cancers. The proposed mutagenic mechanism — that partition failure accelerates mutation accumulation at commitment-relevant regulatory addresses through missegregation and mislicensing of the write/erase chemistry — remains a hypothesis whose direct experimental test has not been performed.

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