PRC1 chromatin factors strengthen the consistency of neuronal cell fate specification and maintenance in C. elegans

ABSTRACT: In the nervous system, the specific identity of a neuron is established and maintained by terminal selector transcription factors that directly activate large batteries of terminal differentiation genes and positively regulate their own expression via feedback loops. However, how this is achieved in a reliable manner despite noise in gene expression, genetic variability or environmental perturbations remains poorly understood. We addressed this question using the AIY cholinergic interneurons of C. elegans, whose specification and differentiation network is well characterized. Via a genetic screen, we found that a loss of function of PRC1 chromatin factors induces a stochastic loss of AIY differentiated state in a small proportion of the population. PRC1 factors act directly in the AIY neuron and independently of PRC2 factors. By quantifying mRNA and protein levels of terminal selector transcription factors in single neurons, using smFISH and CRISPR tagging, we observed that, in PRC1 mutants, terminal selector expression is still initiated during embryonic development but the level is reduced, and expression is subsequently lost in a stochastic manner during maintenance phase in part of the population. We also observed variability in the level of expression of terminal selectors in wild type animals and, using correlation analysis, established that this noise comes from both intrinsic and extrinsic sources. Finally, we found that PRC1 factors increase the resistance of AIY neuron fate to environmental stress, and also secure the terminal differentiation of other neuron types. We propose that PRC1 factors contribute to the consistency of neuronal cell fate specification and maintenance by protecting neurons against noise and perturbations in their differentiation program. Author summary During development, a high diversity of neuronal cell types is produced and they subsequently maintain their identity throughout the life of the animal. How this is achieved in a manner that is both accurate and robust to perturbations remains poorly understood. Terminal selector transcription factors play a key role in the specification and maintenance of neuron type identities. In this study, we observed that their expression is noisy. We also found that PRC1 chromatin factors contribute to the consistency of neuronal cell fate specification and maintenance. They help to set the correct level of terminal selector expression during the specification phase, and they secure the maintenance of terminal selector expression at later stages. PRC1 factors also increase the resistance of neuronal identity to environmental stress.

SUBMITTER: Bordet G 

PROVIDER: S-EPMC9126393 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature