Deciphering a global source of non-genetic heterogeneity in cancer cells

Cell-to-cell variability within a clonal population, also known as non-genetic heterogeneity, has created significant challenges for intervening with diseases such as cancer. While non-genetic heterogeneity can arise from the variability in the expression of specific genes, it remains largely unclear whether and how clonal cells could be heterogeneous in the expression of the entire transcriptome. Here, we showed that gene transcriptional activity is globally modulated in individual cancer cells, leading to non-genetic heterogeneity in the global transcription rate. Such heterogeneity contributes to cell-to-cell variability in transcriptome size and displays both dynamic and static characteristics, with the global transcription rate temporally modulated in a cell-cycle-coupled manner and the time-averaged rate being distinct between cells and heritable across generations. Additional evidence indicated the role of ATP metabolism in this heterogeneity, and suggested its implication in intrinsic cancer drug tolerance. Collectively, our work shed light on the mode, mechanism, and implication of a global but often hidden source of non-genetic heterogeneity.

Automated summary

This study reveals the presence of non-genetic heterogeneity within cancer cells, which is characterized by global modulation of gene transcriptional activity. This heterogeneity contributes to variability in the transcriptome size and shows both dynamic and static characteristics. ATP metabolism is suggested to play a role in this heterogeneity, with implications for cancer drug tolerance.