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

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 mathemat...

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Autores principales: Soto, Ximena, Biga, Veronica, Kursawe, Jochen, Lea, Robert, Doostdar, Parnian, Thomas, Riba, Papalopulu, Nancy
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298297/
https://www.ncbi.nlm.nih.gov/pubmed/32395844
http://dx.doi.org/10.15252/embj.2019103558
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author Soto, Ximena
Biga, Veronica
Kursawe, Jochen
Lea, Robert
Doostdar, Parnian
Thomas, Riba
Papalopulu, Nancy
author_facet Soto, Ximena
Biga, Veronica
Kursawe, Jochen
Lea, Robert
Doostdar, Parnian
Thomas, Riba
Papalopulu, Nancy
author_sort Soto, Ximena
collection PubMed
description 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.
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spelling pubmed-72982972020-06-17 Dynamic properties of noise and Her6 levels are optimized by miR‐9, allowing the decoding of the Her6 oscillator Soto, Ximena Biga, Veronica Kursawe, Jochen Lea, Robert Doostdar, Parnian Thomas, Riba Papalopulu, Nancy EMBO J Articles 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. John Wiley and Sons Inc. 2020-05-12 2020-06-17 /pmc/articles/PMC7298297/ /pubmed/32395844 http://dx.doi.org/10.15252/embj.2019103558 Text en © 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 http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
Soto, Ximena
Biga, Veronica
Kursawe, Jochen
Lea, Robert
Doostdar, Parnian
Thomas, Riba
Papalopulu, Nancy
Dynamic properties of noise and Her6 levels are optimized by miR‐9, allowing the decoding of the Her6 oscillator
title Dynamic properties of noise and Her6 levels are optimized by miR‐9, allowing the decoding of the Her6 oscillator
title_full Dynamic properties of noise and Her6 levels are optimized by miR‐9, allowing the decoding of the Her6 oscillator
title_fullStr Dynamic properties of noise and Her6 levels are optimized by miR‐9, allowing the decoding of the Her6 oscillator
title_full_unstemmed Dynamic properties of noise and Her6 levels are optimized by miR‐9, allowing the decoding of the Her6 oscillator
title_short Dynamic properties of noise and Her6 levels are optimized by miR‐9, allowing the decoding of the Her6 oscillator
title_sort dynamic properties of noise and her6 levels are optimized by mir‐9, allowing the decoding of the her6 oscillator
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298297/
https://www.ncbi.nlm.nih.gov/pubmed/32395844
http://dx.doi.org/10.15252/embj.2019103558
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