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Dynamic properties of noise and Her6 levels are optimized by miR-9, allowing the decoding of the Her6 oscillator

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Soto_2020_EMBOJ_Dynamic_CC.pdf (4.283Mb)
Date
17/06/2020
Author
Soto, Ximena
Biga, Veronica
Kursawe, Jochen
Lea, Robert
Doostdar, Parnian
Thomas, Riba
Papalopulu, Nancy
Keywords
Cell state transitions
Gene expression noise
Her6 oscillations
miR-9
Zebrafish neurogenesis
QH301 Biology
DAS
BDC
R2C
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Abstract
Noise is prevalent in biology and has been widely quantified using snapshot measurements. This static view obscures our understanding of dynamic noise properties and how these affect gene expression and cell state transitions. Using a CRISPR/Cas9 Zebrafish her6::Venus reporter combined with mathematical and in vivo experimentation, we explore how noise affects the protein dynamics of Her6, a basic helix‐loop‐helix transcriptional repressor. During neurogenesis, Her6 expression transitions from fluctuating to oscillatory at single‐cell level. We identify that absence of miR‐9 input generates high‐frequency noise in Her6 traces, inhibits the transition to oscillatory protein expression and prevents the downregulation of Her6. Together, these impair the upregulation of downstream targets and cells accumulate in a normally transitory state where progenitor and early differentiation markers are co‐expressed. Computational modelling and double smFISH of her6 and the early neurogenesis marker, elavl3, suggest that the change in Her6 dynamics precedes the downregulation in Her6 levels. This sheds light onto the order of events at the moment of cell state transition and how this is influenced by the dynamic properties of noise. Our results suggest that Her/Hes oscillations, facilitated by dynamic noise optimization by miR‐9, endow progenitor cells with the ability to make a cell state transition.
Citation
Soto , X , Biga , V , Kursawe , J , Lea , R , Doostdar , P , Thomas , R & Papalopulu , N 2020 , ' Dynamic properties of noise and Her6 levels are optimized by miR-9, allowing the decoding of the Her6 oscillator ' , EMBO Journal , vol. 39 , no. 12 , e103558 . https://doi.org/10.15252/embj.2019103558
Publication
EMBO Journal
Status
Peer reviewed
DOI
https://doi.org/10.15252/embj.2019103558
ISSN
0261-4189
Type
Journal article
Rights
Copyright © 2020 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Description
This work was supported by a Wellcome Trust Senior Research Fellowship to NP (106185/Z/14/Z).
Collections
  • University of St Andrews Research
URL
https://www.embopress.org/doi/full/10.15252/embj.2019103558#support-information-section
URI
http://hdl.handle.net/10023/19941

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