A ubiquitous feature of the circadian clock across life forms is its organization as a network of cellular oscillators, with individual cellular oscillators within the network often exhibiting considerable heterogeneity in their intrinsic periods. The interaction of coupling and heterogeneity in circadian clock networks is hypothesized to influence clock’s entrainability, but our knowledge of mechanisms governing period heterogeneity within circadian clock networks remains largely elusive. In this study, we aimed to explore the principles that underlie intercellular period variation in circadian clock networks (clonal period heterogeneity). To this end, we employed a laboratory selection approach and derived a panel of 25 clonal cell populations exhibiting circadian periods ranging from 22 to 28 h. We report that a single parent clone can produce progeny clones with a wide distribution of circadian periods, and this heterogeneity, in addition to being stochastically driven, has a heritable component. By quantifying the expression of 20 circadian clock and clock-associated genes across our clone panel, we found that inheritance of expression patterns in at least three clock genes might govern clonal period heterogeneity in circadian clock networks. Furthermore, we provide evidence suggesting that heritable epigenetic variation in gene expression regulation might underlie period heterogeneity.

生物钟在生命周期中普遍存在的特征是其组织为细胞振荡器网络，网络中的各个细胞振荡器通常在其固有周期内表现出相当大的异质性。假设昼夜时钟网络中耦合和异质性的相互作用会影响时钟的可携带性，但我们对昼夜时钟网络中控制周期异质性的机制的了解仍然很少。在这项研究中，我们旨在探索生物钟时钟网络中细胞间周期变化的基础（克隆周期异质性）。为此，我们采用了实验室选择方法，并得出了25个克隆细胞群体，它们的昼夜周期范围为22至28小时。我们报告单个亲本克隆可以产生昼夜节律周期的广泛分布的后代克隆，这种异质性，除了受到随机驱动外，还具有可遗传的成分。通过量化整个克隆组中20个生物钟和生物钟相关基因的表达，我们发现至少三个生物钟基因中表达模式的遗传可能会控制生物钟网络中的克隆周期异质性。此外，我们提供的证据表明，基因表达调控中可遗传的表观遗传变异可能是周期异质性的基础。通过量化整个克隆组中20个生物钟和生物钟相关基因的表达，我们发现至少三个生物钟基因中表达模式的遗传可能会控制生物钟网络中的克隆周期异质性。此外，我们提供的证据表明，基因表达调控中可遗传的表观遗传变异可能是周期异质性的基础。通过量化整个克隆组中20个生物钟和生物钟相关基因的表达，我们发现至少三个生物钟基因中表达模式的遗传可能会控制生物钟网络中的克隆周期异质性。此外，我们提供的证据表明，基因表达调控中可遗传的表观遗传变异可能是周期异质性的基础。