Mechanism of life-long maintenance of neuron identity despite molecular fluctuations

Joleen J.H. Traets, Servaas N. van der Burght, Suzanne Rademakers, Gert Jansen, Jeroen S. van Zon*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Cell fate is maintained over long timescales, yet molecular fluctuations can lead to spontaneous loss of this differentiated state. Our simulations identified a possible mechanism that explains life-long maintenance of ASE neuron fate in C. elegans by the terminal selector transcription factor CHE-1. Here, fluctuations in CHE-1 level are buffered by the reservoir of CHE-1 bound at its target promoters, which ensures continued che-1 expression by preferentially binding the che-1 promoter. We provide experimental evidence for this mechanism by showing that che-1 expression was resilient to induced transient CHE-1 depletion, while both expression of CHE-1 targets and ASE function were lost. We identified a 130 bp che-1 promoter fragment responsible for this resilience, with deletion of a homeodomain binding site in this fragment causing stochastic loss of ASE identity long after its determination. Because network architectures that support this mechanism are highly conserved in cell differentiation, it may explain stable cell fate maintenance in many systems.

Original languageEnglish
Article numbere66955
JournaleLife
Volume10
DOIs
Publication statusPublished - Dec 2021

Bibliographical note

Funding Information:
Some strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440), and the Mitani laboratory through the National Bio-Resource Project of the MEXT, Japan. We thank Dylan Rahe (Hobert lab) for providing the GFP-tagged che-1(ot856) allele. This work is part of the research program of the Foundation for Fundamental Research on Matter (FOM; grant FOM-161, 14NOISE05), which is financially supported by the Netherlands Organization for Scientific Research (NWO).

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