Stochastic fluctuations and distributed control of gene expression impact cellular memory.

Guillaume Corre,Ophélie Arnaud,Gaël Kaneko,José Viñuelas,Guillaume Beslon,András Paldi,Olivier Gandrillon,Jean-Jacques Kupiec,Daniel Stockholm,Thi My Anh Neildez-Nguyen,Yoshiaki Yamagata

doi:10.1371/journal.pone.0115574

Abstract

Despite the stochastic noise that characterizes all cellular processes the cells are able to maintain and transmit to their daughter cells the stable level of gene expression. In order to better understand this phenomenon, we investigated the temporal dynamics of gene expression variation using a double reporter gene model. We compared cell clones with transgenes coding for highly stable mRNA and fluorescent proteins with clones expressing destabilized mRNA-s and proteins. Both types of clones displayed strong heterogeneity of reporter gene expression levels. However, cells expressing stable gene products produced daughter cells with similar level of reporter proteins, while in cell clones with short mRNA and protein half-lives the epigenetic memory of the gene expression level was completely suppressed. Computer simulations also confirmed the role of mRNA and protein stability in the conservation of constant gene expression levels over several cell generations. These data indicate that the conservation of a stable phenotype in a cellular lineage may largely depend on the slow turnover of mRNA-s and proteins.

Highlights

Specific gene regulation mechanisms are believed to ensure a constant expression level and guarantee long-term phenotypic stability of the cells and cell lineages
We verified if the differences of the yellow fluorescent protein (YFP) and cyan fluorescent protein (CFP) protein levels between the cells reflect the transcription of the genes
The relative level of transcripts correlated well with the average fluorescence intensity and no YFP and CFP transcripts were detected in non-fluorescent cells

Summary

Introduction

Specific gene regulation mechanisms are believed to ensure a constant expression level and guarantee long-term phenotypic stability of the cells and cell lineages. MRNA and protein levels in vary widely even between cells of a clonal populations exposed to a homogenous environment. This general phenomenon that concerns every gene in every cell type of multicellular organisms poses a challenge to our understanding of the phenotypic stability of the cell [2]. The difficulty is similar if we want to explain how a phenotype can be stably transmitted over cell divisions in a cell lineage This role is typically attributed to memory mechanisms of gene transcription regulation [4].

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Results

Conclusion