细胞群体中的细胞间变异性，即非遗传性异质性，给干预癌症等疾病带来了重大挑战。尽管非遗传性异质性可能源于特定基因表达的变异性，但目前尚不清楚克隆细胞在整个转录组表达上是否存在异质性以及存在的方式。在本文中，我们展示了基因转录活性在个体癌细胞中全局调节，导致全局转录速率的非遗传性异质性。这种异质性促进了转录组大小的细胞间变异性，并显示出动态和静态特征，全局转录速率在细胞周期耦合的方式下时间上调节，并且在细胞间具有遗传性传递。额外的证据表明，ATP代谢在这种异质性中起到了作用，并暗示其在内在癌症药物耐受性中的意义。综上所述，我们的研究揭示了一种全局但常常隐藏的非遗传性异质性的模式、机制和意义。© 2023年，由牛津大学出版社代表核酸研究杂志出版。

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.© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.