Number of active transcription factor binding sites is essential for the Hes7 oscillator

Theoretical Biology & Medical Modelling
Stefan ZeiserG Winkler

Abstract

It is commonly accepted that embryonic segmentation of vertebrates is regulated by a segmentation clock, which is induced by the cycling genes Hes1 and Hes7. Their products form dimers that bind to the regulatory regions and thereby repress the transcription of their own encoding genes. An increase of the half-life of Hes7 protein causes irregular somite formation. This was shown in recent experiments by Hirata et al. In the same work, numerical simulations from a delay differential equations model, originally invented by Lewis, gave additional support. For a longer half-life of the Hes7 protein, these simulations exhibited strongly damped oscillations with, after few periods, severely attenuated the amplitudes. In these simulations, the Hill coefficient, a crucial model parameter, was set to 2 indicating that Hes7 has only one binding site in its promoter. On the other hand, Bessho et al. established three regulatory elements in the promoter region. We show that--with the same half life--the delay system is highly sensitive to changes in the Hill coefficient. A small increase changes the qualitative behaviour of the solutions drastically. There is sustained oscillation and hence the model can no longer explain the disruption o...Continue Reading

References

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Citations

Sep 10, 2011·BMC Systems Biology·Wei ZhouYonghua Wang
Aug 23, 2012·PLoS Biology·Christian SchröterAndrew C Oates
May 27, 2009·PLoS Computational Biology·Smita AgrawalDavid V Schaffer
Jul 5, 2012·PLoS Computational Biology·Hendrik B TiedemannMartin Hrabě de Angelis
Nov 7, 2007·Computational Biology and Chemistry·S ZeiserG Winkler
Nov 23, 2017·Nucleic Acids Research·Sridevi RanganathanKathleen A McDonough
Oct 2, 2009·Developmental Dynamics : an Official Publication of the American Association of Anatomists·Tim Brend, Scott A Holley
Apr 27, 2011·Physical Review. E, Statistical, Nonlinear, and Soft Matter Physics·I PotapovA Kuznetsov
Oct 3, 2014·PLoS Computational Biology·Hendrik B TiedemannMartin Hrabě de Angelis
Mar 23, 2013·Molecular BioSystems·Henglin SongTianshou Zhou
Jul 24, 2007·Mechanisms of Development·Olivier Cinquin

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Software Mentioned

MATLAB

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