title: Modeling the dynamics of hypoxia inducible factor-1α (HIF-1α) within single cells and 3D cell culture systems.
abstract: HIF (hypoxia inducible factor) is an oxygen-regulated transcription factor that mediates the intracellular response to hypoxia in human cells. There is increasing evidence that cell signaling pathways encode temporal information, and thus cell fate may be determined by the dynamics of protein levels. We have developed a mathematical model to describe the transient dynamics of the HIF-1α protein measured in single cells subjected to hypoxic shock. The essential characteristics of these data are modeled with a system of differential equations describing the feedback inhibition between HIF-1α and prolyl hydroxylases (PHD) oxygen sensors. Heterogeneity in the single-cell data is accounted through parameter variation in the model. We previously identified the PHD2 isoform as the main PHD sensor responsible for controlling the HIF-1α transient response, and make here testable predictions regarding HIF-1α dynamics subject to repetitive hypoxic pulses. The model is further developed to describe the dynamics of HIF-1α in cells cultured as 3D spheroids, with oxygen dynamics parameterized using experimental measurements of oxygen within spheroids. We show that the dynamics of HIF-1α and transcriptional targets of HIF-1α display a non-monotone response to the oxygen dynamics. Specifically we demonstrate that the dynamic transient behavior of HIF-1α results in differential dynamics in transcriptional targets.
authors.affiliation: Department of Mathematical Sciences, University of Liverpool, Liverpool L69 7ZL, UK.
authors.forename: Joseph
authors.initials: J
authors.lastname: Leedale
authors.affiliation: Department of Biochemistry, Centre for Cell Imaging, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK.
authors.forename: Anne
authors.initials: A
authors.lastname: Herrmann
authors.affiliation: Department of Biochemistry, Centre for Cell Imaging, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK.
authors.forename: James
authors.initials: J
authors.lastname: Bagnall
authors.affiliation: Biochemistry and Cell Biology, University College, Cork, Ireland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Fercher
authors.affiliation: Biochemistry and Cell Biology, University College, Cork, Ireland.
authors.forename: Dmitri
authors.initials: D
authors.lastname: Papkovsky
authors.affiliation: Department of Biochemistry, Centre for Cell Imaging, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK.
authors.forename: Violaine
authors.initials: V
authors.lastname: Sée
authors.affiliation: Department of Mathematical Sciences, University of Liverpool, Liverpool L69 7ZL, UK. Electronic address: rbearon@liverpool.ac.uk.
authors.forename: Rachel N
authors.initials: RN
authors.lastname: Bearon
mesh_terms: D000818:Animals; D006367:HeLa Cells; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008962:Models, Theoretical
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit
keywords: HIF (hypoxia inducible factor); Hypoxia; Mathematical modeling; Oxygen nanoprobes; Prolyl hydroxylase; Spheroids