Widespread transcriptional memory shapes heritable states and functional heterogeneity in cancer and stem cells [RNA-Seq]

Recent studies show that non-genetic heterogeneity, particularly through heritable cell states, shapes cancer evolution and developmental trajectories. However, single-cell snapshots lack temporal information to identify these states. We employ lineage-resolved single-cell transcriptomics to map heritable cell states that persist across divisions, distinguishing them from transient fluctuations. We uncover that heritable states are underpinned by widespread transcriptional memory, whereby heritable gene expression defines two classes of states: clustered states, characterized by clustered gene expression, and latent states, marked by non-clustered gene expression. This memory shows conservation across cell types and conditions and appears to be maintained by robust epigenetic mechanisms resistant to environmental perturbations. Functionally, memory genes predict critical behaviors including metastatic potential and lineage commitment, with latent-state genes often outperforming clustered-state genes. Our findings establish transcriptional memory as a potential basis of heritable cellular heterogeneity, providing a framework for understanding functional cellular variations across biological systems. A record of this paper’s transparent peer review process is included in the supplemental information.