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

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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
JournalPloS ONE
Volume11
Issue number10
DOIs
Publication statusPublished - 31 Oct 2016

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DNA replication
Robust control
DNA Replication
Gene expression
histones
Histones
Feedback control
Gene Expression
gene expression
DNA
Proteins
synthesis
S Phase
proteins
interphase
Ensure
Genes
RNA
human development
Genomic Instability

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Modelling Robust Feedback Control Mechanisms That Ensure Reliable Coordination of Histone Gene Expression with DNA Replication. / Christopher, Andrea; Hameister, Heike; Corrigall, Holly; Ebenhoeh, Oliver; Muller, Berndt; Ullner, Ekkehard.

In: PloS ONE, Vol. 11, No. 10, e0165848, 31.10.2016.

Research output: Contribution to journalArticle

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