TY - JOUR
T1 - A novel mathematical method for disclosing oscillations in gene transcription
T2 - A comparative study
AU - Antoulas, Athanasios C.
AU - Zhu, Bokai
AU - Zhang, Qiang
AU - York, Brian
AU - O’Malley, Bert W.
AU - Dacso, Clifford
N1 - Funding Information:
This work was supported by National Science Foundation, CCF-1320866 to Antoulas; German Science Foundation, AN-693/1-1 to Antoulas; Max-Planck Institut für Physik Komplexer Systeme, Antoulas; NIDDK U24 DK097748 to York; NIDDK, U24 DK097748 to O’Malley; NIDDK HD07857 to O’Malley; Center for the Advancement of Science in Space, GA-2014-136, to Dacso and York; Brockman Medical Research Foundation to Dacso, O’Malley, York, Zhu; Phillip J. Carroll, Jr. Professorship to Dacso; Joyce Family Foundation to Dacso; Sonya and William Carpenter to Dacso, and National Science Foundation CISE-11703170. Bokai Zhu was supported by Junior Faculty Development award 1-18-JDF-025 from the American Diabetes Association. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2018 Antoulas et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2018/9
Y1 - 2018/9
N2 - Circadian rhythmicity, the 24-hour cycle responsive to light and dark, is determined by periodic oscillations in gene transcription. This phenomenon has broad ramifications in physiologic function. Recent work has disclosed more cycles in gene transcription, and to the uncovering of these we apply a novel signal processing methodology known as the pencil method and compare it to conventional parametric, nonparametric, and statistical methods. Methods: In order to assess periodicity of gene expression over time, we analyzed a database derived from livers of mice entrained to a 12-hour light/12-hour dark cycle. We also analyzed artificially generated signals to identify differences between the pencil decomposition and other alternative methods. Results: The pencil decomposition revealed hitherto-unsuspected oscillations in gene transcription with 12-hour periodicity. The pencil method was robust in detecting the 24-hour circadian cycle that was known to exist, as well as confirming the existence of shorter-period oscillations. A key consequence of this approach is that orthogonality of the different oscillatory components can be demonstrated. thus indicating a biological independence of these oscillations, that has been subsequently confirmed empirically by knocking out the gene responsible for the 24-hour clock. Conclusion: System identification techniques can be applied to biological systems and can uncover important characteristics that may elude visual inspection of the data. Significance: The pencil method provides new insights on the essence of gene expression and discloses a wide variety of oscillations in addition to the well-studied circadian pattern. This insight opens the door to the study of novel mechanisms by which oscillatory gene expression signals exert their regulatory effect on cells to influence human diseases.
AB - Circadian rhythmicity, the 24-hour cycle responsive to light and dark, is determined by periodic oscillations in gene transcription. This phenomenon has broad ramifications in physiologic function. Recent work has disclosed more cycles in gene transcription, and to the uncovering of these we apply a novel signal processing methodology known as the pencil method and compare it to conventional parametric, nonparametric, and statistical methods. Methods: In order to assess periodicity of gene expression over time, we analyzed a database derived from livers of mice entrained to a 12-hour light/12-hour dark cycle. We also analyzed artificially generated signals to identify differences between the pencil decomposition and other alternative methods. Results: The pencil decomposition revealed hitherto-unsuspected oscillations in gene transcription with 12-hour periodicity. The pencil method was robust in detecting the 24-hour circadian cycle that was known to exist, as well as confirming the existence of shorter-period oscillations. A key consequence of this approach is that orthogonality of the different oscillatory components can be demonstrated. thus indicating a biological independence of these oscillations, that has been subsequently confirmed empirically by knocking out the gene responsible for the 24-hour clock. Conclusion: System identification techniques can be applied to biological systems and can uncover important characteristics that may elude visual inspection of the data. Significance: The pencil method provides new insights on the essence of gene expression and discloses a wide variety of oscillations in addition to the well-studied circadian pattern. This insight opens the door to the study of novel mechanisms by which oscillatory gene expression signals exert their regulatory effect on cells to influence human diseases.
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U2 - 10.1371/journal.pone.0198503
DO - 10.1371/journal.pone.0198503
M3 - Article
C2 - 30231032
AN - SCOPUS:85053623984
VL - 13
JO - PLoS ONE
JF - PLoS ONE
SN - 1932-6203
IS - 9
M1 - e0198503
ER -