Dynamic properties of noise and Her6 levels are optimized by miR‐9, allowing the decoding of the Her6 oscillator. (12th May 2020) - Soto, Ximena
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. Synopsis: In neuronal progenitors, oscillatory expression of transcription regulators mediates transition to a differentiated state. This study shows that miR‐9 drives zebrafish neurogenesis by counteracting noise and establishing oscillations in expression of the repressor Her6. Live imaging of an endogenous Her6 reporter reveals the dynamic properties of Her6 protein expression and noise at the single‐cell level. miR‐9 counteracts high‐frequency noise of Her6 expression, permitting the emergence and function of Her6 oscillations. Loss of miR‐9 regulation inhibits neural differentiation, and neural progenitors accumulate in a transitory state Cell state transitions appear sensitive to short time‐scale protein dynamics. Abstract : Live imaging at single‐cell resolution shows that miR‐9 counteracts noise in oscillatory expression of transcriptional repressor Her6 to drive neural progenitor differentiation in zebrafish hindbrain.