title: Modelling Robust Feedback Control Mechanisms That Ensure Reliable Coordination of Histone Gene Expression with DNA Replication.
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.
authors: School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen Foresterhill, Aberdeen, Scotland, United Kingdom.
authors: Andrea
authors: A
authors: Christopher
authors: Department of Physics (SUPA) and Institute for Complex Systems and Mathematical Biology (ICSMB), University of Aberdeen, Aberdeen, Scotland, United Kingdom.
authors: Heike
authors: H
authors: Hameister
authors: School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen Foresterhill, Aberdeen, Scotland, United Kingdom.
authors: Holly
authors: H
authors: Corrigall
authors: School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen Foresterhill, Aberdeen, Scotland, United Kingdom.|Institute of Quantitative and Theoretical Biology, Cluster of Excellence on Plant Sciences (CEPLAS), Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.
authors: Oliver
authors: O
authors: Ebenhöh
authors: School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen Foresterhill, Aberdeen, Scotland, United Kingdom.
authors: Berndt
authors: B
authors: Müller
authors: School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen Foresterhill, Aberdeen, Scotland, United Kingdom.|Department of Physics (SUPA) and Institute for Complex Systems and Mathematical Biology (ICSMB), University of Aberdeen, Aberdeen, Scotland, United Kingdom.
authors: Ekkehard
authors: http://orcid.org/0000-0002-6306-4218
authors: E
authors: Ullner
mesh_terms: D000465:Algorithms; D002453:Cell Cycle / Q000235:genetics; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000235:genetics* / Q000378:metabolism*; D004261:DNA Replication; D005786:Gene Expression Regulation; D006657:Histones / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D012333:RNA, Messenger / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; D006657:Histones; D012333:RNA, Messenger; D004247:DNA