Heritable gene expression variability and stochasticity govern clonal heterogeneity in circadian period
Open Access
- 3 August 2020
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Biology
- Vol. 18 (8), e3000792
- https://doi.org/10.1371/journal.pbio.3000792
Abstract
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.Funding Information
- Deutsche Forschungsgemeinschaft (SFB740/D2)
- Deutsche Forschungsgemeinschaft (TRR186/P17)
- Alexander von Humboldt-Stiftung
This publication has 94 references indexed in Scilit:
- Cellular Heterogeneity: Do Differences Make a Difference?Cell, 2010
- Circadian-independent cell mitosis in immortalized fibroblastsProceedings of the National Academy of Sciences of the United States of America, 2010
- Fast and accurate long-read alignment with Burrows–Wheeler transformBioinformatics, 2010
- A Genome-wide RNAi Screen for Modifiers of the Circadian Clock in Human CellsCell, 2009
- Preferential Inhibition of BMAL2-CLOCK Activity by PER2 Reemphasizes Its Negative Role and a Positive Role of BMAL2 in the Circadian TranscriptionOnline Journal of Public Health Informatics, 2009
- Nature, Nurture, or Chance: Stochastic Gene Expression and Its ConsequencesCell, 2008
- Isoform-selective histone deacetylase inhibitorsChemical Society Reviews, 2008
- Separate oscillating cell groups in mouse suprachiasmatic nucleus couple photoperiodically to the onset and end of daily activityProceedings of the National Academy of Sciences of the United States of America, 2007
- Molecular mechanism of suppression of circadian rhythms by a critical stimulusThe EMBO Journal, 2006
- Oscillations and variability in the p53 systemMolecular Systems Biology, 2006