TY - JOUR
T1 - Noise-driven cellular heterogeneity in circadian periodicity
AU - Li, Yan
AU - Shan, Yongli
AU - Desai, Ravi V.
AU - Cox, Kimberly H.
AU - Weinberger, Leor S.
AU - Takahashi, Joseph S.
N1 - Funding Information:
ACKNOWLEDGMENTS. This research was supported by the Howard Hughes Medical Institute. The noise enhancer molecule was developed with the support of NIH grant AI109593. We thank Dr. John H. Abel and Dr. Francis J. Doyle III from Harvard Medical School for their help with the single-cell imaging analysis pipeline, Gokhul Kilaru for bioinformatics support, and all J.S.T. laboratory members, Dr. Carla B. Green, and Dr. Shin Yamazaki for helpful discussions. J.S.T. is an Investigator in the Howard Hughes Medical Institute.
PY - 2020/5/12
Y1 - 2020/5/12
N2 - Nongenetic cellular heterogeneity is associated with aging and disease. However, the origins of cell-to-cell variability are complex and the individual contributions of different factors to total phenotypic variance are still unclear. Here, we took advantage of clear phenotypic heterogeneity of circadian oscillations in clonal cell populations to investigate the underlying mechanisms of cell-to-cell variability. Using a fully automated tracking and analysis pipeline, we examined circadian period length in thousands of single cells and hundreds of clonal cell lines and found that longer circadian period is associated with increased intercellular heterogeneity. Based on our experimental results, we then estimated the contributions of heritable and nonheritable factors to this variation in circadian period length using a variance partitioning model. We found that nonheritable noise predominantly drives intercellular circadian period variation in clonal cell lines, thereby revealing a previously unrecognized link between circadian oscillations and intercellular heterogeneity. Moreover, administration of a noise-enhancing drug reversibly increased both period length and variance. These findings suggest that circadian period may be used as an indicator of cellular noise and drug screening for noise control.
AB - Nongenetic cellular heterogeneity is associated with aging and disease. However, the origins of cell-to-cell variability are complex and the individual contributions of different factors to total phenotypic variance are still unclear. Here, we took advantage of clear phenotypic heterogeneity of circadian oscillations in clonal cell populations to investigate the underlying mechanisms of cell-to-cell variability. Using a fully automated tracking and analysis pipeline, we examined circadian period length in thousands of single cells and hundreds of clonal cell lines and found that longer circadian period is associated with increased intercellular heterogeneity. Based on our experimental results, we then estimated the contributions of heritable and nonheritable factors to this variation in circadian period length using a variance partitioning model. We found that nonheritable noise predominantly drives intercellular circadian period variation in clonal cell lines, thereby revealing a previously unrecognized link between circadian oscillations and intercellular heterogeneity. Moreover, administration of a noise-enhancing drug reversibly increased both period length and variance. These findings suggest that circadian period may be used as an indicator of cellular noise and drug screening for noise control.
KW - Circadian oscillation
KW - Heterogeneity/ variance
KW - Period
KW - Single-cell imaging
KW - Transcriptional noise
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U2 - 10.1073/pnas.1922388117
DO - 10.1073/pnas.1922388117
M3 - Article
C2 - 32358201
AN - SCOPUS:85084506051
VL - 117
SP - 10350
EP - 10356
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 19
ER -