Stochastic Noise in Gene Expression Impacts Developmental Self-organization

Giri, Ritika

doi:https://doi.org/10.21985/n2-fbm3-mt41

Work

Stochastic Noise in Gene Expression Impacts Developmental Self-organization

Public

Download PDF

Download All Files (.zip)

Cells are often precisely organized into patterns within developing tissues. This precision must emerge from biochemical processes within, and between cells, that are inherently stochastic. I investigated the impact of stochastic gene expression on self-organized pattern formation, focusing on Senseless (Sens), a key target of Wnt and Notch signaling during Drosophila sensory development. Using a two-color reporter system to directly decouple intrinsic and extrinsic noise sources, I counted Sens protein molecule numbers in several thousand cells undergoing a developmental transit. This approach provided the necessary statistical power to yield a high-resolution profile of the complex architecture of stochastic noise across the spectrum of Sens expression. Experimentally measured gene expression rate constants were then used to build a simulation model to predict Sens noise profiles for different perturbations. Experimental validation of the model provided a coherent view of how translation, and transcription events, influence noise. Stochastic birth-death events of mRNA and protein molecules contributed to a uniform level of Fano noise. This was validated by perturbing microRNA regulation of sens. In contrast, stochastic bursts of transcription produced high noise, but only in cells with low Sens. Transcription bursts were enhanced when both sens alleles were present in homologous loci that promoted trans allelic interactions. To understand the consequences of stochastic sens gene expression, I asked if self-organized patterning is helped or hindered by stochastic noise. Loss of microRNA repression of sens increased Sens protein abundance, but not sensory pattern disorder. However, enhanced transcription noise in a subset of cells, arising from allelic interactions, led to disordered patterning. I observed that unexpectedly few numbers of fate determinant molecules are required to make this particular fate decision. Intriguingly, cells experienced very large fluctuations in this critical regime, between 30-50% in relative magnitude. A simulation model of fate selection revealed that the presence of stochastic noise might reduce the time required for pattern resolution during self-organization. Taken together, this suggests that gene expression stochasticity is a critical feature, that must be constrained during development, so as to minimize the time and energy required to transit, while maximizing the robustness of the final pattern.

Creator