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.
Original language | English |
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Article number | e103558 |
Number of pages | 23 |
Journal | EMBO Journal |
Volume | 39 |
Issue number | 12 |
Early online date | 12 May 2020 |
DOIs | |
Publication status | Published - 17 Jun 2020 |
Keywords
- Cell state transitions
- Gene expression noise
- Her6 oscillations
- miR-9
- Zebrafish neurogenesis