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EMBO J
2020 Jun 17;3912:e103558. doi: 10.15252/embj.2019103558.
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Dynamic properties of noise and Her6 levels are optimized by miR-9, allowing the decoding of the Her6 oscillator.
Soto X, Biga V, Kursawe J, Lea R, Doostdar P, Thomas R, Papalopulu N.
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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.
Figure 1. Her6::Venus protein expression during Zebrafish neural development
A. B. C. D–F. G. H. I. J, K. L.
Figure 2. Dynamics of Her6::Venus in single neural progenitor cells
A. B. C. D. E. F–I.
Figure EV1. Single‐cell dynamics of Her6::Venus observed in progenitors at different stages in development. Related to Fig 2
A, B.
Figure EV2. Power analysis of Her6::Venus in progenitors at different stages in development. Related to Fig 2
A. B.
Figure 3. A mutation of the miR‐9 binding site affects Her6 level over the course of development
A. B. C. D. E. F. G.
Figure 4. A mutation of the miR‐9 binding site affects Her6 dynamics at single cell level
A, B. C. D. E. F, G. H. I. J.
Figure EV3. Single cell dynamics of Her6::Venus observed in progenitors in the presence and absence of miR‐9 regulation. Related to Fig 4
A, B.
Figure EV4. Frequency analysis of Her6::Venus observed in progenitors in the presence and absence of miR‐9 regulation. Related to Fig 4
A, B. C. D, E. F. G.
Figure 5. Mathematical model exploring the effect of changes in Her6 dynamics on a downstream target
A. B. C. D. E. F.
Figure 6. Changes in cell fate decisions in the absence of miR‐9 regulation
A. B. C. D. E. F–H. I. J.
Figure 7. The role of miRâ€9 regulation on Her6 dynamic expression during hindbrain development
A. B.
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