A high-density lineage tree reveals dynamics of expression differences accumulation in nondifferentiating clonal expansion

Differences in gene expression levels among genetically identical cells naturally accumulate during cellular proliferation, forming the basis of expression noise or differentiation. Nevertheless, how transcriptome-wide noise accumulation is constrained to maintain homeostasis during continuous cell divisions has remained largely unresolved. We developed a novel method named "single-cell transcriptome and dense tree" (STADT) to simultaneously determines the transcriptomes and lineage tree of >50% single cells in a single-cell-seeded colony. This lineage tree revealed gradual accumulation of transcriptome differences that became saturated upon four cell divisions, reduced expression noise for sub-tree/sub-colonies closer to inferred expression boundaries, and transcriptionally modulated co-fluctuations among genes. These results collectively showed, for the first time, constrained dynamics of expression noise in the context of cell division.