Modelling Robust Feedback Control Mechanisms That Ensure Reliable Coordination of Histone Gene Expression with DNA Replication

Andrea Christopher, Heike Hameister, Holly Corrigall, Oliver Ebenhoeh, Berndt Muller, Ekkehard Ullner* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)
9 Downloads (Pure)

Abstract

Histone proteins are key elements in the packing of eukaryotic DNA into chromosomes. A little understood control system ensures that histone gene expression is balanced with DNA replication so that histone proteins are produced in appropriate amounts. Disturbing or disrupting this system affects genome stability and gene expression, and has detrimental consequences for human development and health. It has been proposed that feedback control involving histone proteins contributes to this regulation and there is evidence implicating cell cycle checkpoint molecules activated when DNA synthesis is impaired in this control. We have developed mathematical models that incorporate these control modes in the form of inhibitory feedback of histone gene expression from free histone proteins, and alternatively a direct link that couples histone RNA synthesis to DNA synthesis. Using our experimental evidence and related published data we provide a simplified description of histone protein synthesis during S phase. Both models reproduce the coordination of histone gene expression with DNA replication during S phase and the down-regulation of histone RNA when DNA synthesis is interrupted, but only the model incorporating histone protein feedback control was able to effectively simulate the coordinate expression of a simplified histone gene family. Our combined theoretical and experimental approach supports the hypothesis that the regulation of histone gene expression involves feedback control.
Original languageEnglish
Article numbere0165848
Number of pages20
JournalPloS ONE
Volume11
Issue number10
DOIs
Publication statusPublished - 31 Oct 2016

Bibliographical note

Funding: Andrea Christopher was supported by the University of Aberdeen through a Milner Studentship. Heike Hameister was supported by a Postgraduate Research Studentship of the University of Aberdeen. Oliver Ebenhöh was supported by the University of Aberdeen and the Deutsche Forschungsgemeinschaft [Cluster of Excellence on Plant Sciences, CEPLAS (EXC 1028)]. Berndt Müller was supported by the University of Aberdeen. Ekkehard Ullner was supported by the Scottish Universities Life Sciences Alliance (SULSA). The funders provided support in the form of salaries for authors but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. Heike Hameister is currently employed by Merck Serono GmbH. Merck Serono GmbH did not provide any support for this work and did not have any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

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