The Homeobox Genes of Caenorhabditis elegans and Insights into Their Spatio-Temporal Expression Dynamics during Embryogenesis

Hench, Jürgen; Henriksson, Johan; Abou-Zied, Akram M.; Lüppert, Martin; Dethlefsen, Johan; Mukherjee, Krishanu; Tong, Yong Guang; Tang, Lois; Gangishetti, Umesh; Baillie, David L.; Bürglin, Thomas R.

doi:10.1371/journal.pone.0126947

Cited by 31 publications

(33 citation statements)

References 96 publications

(133 reference statements)

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“…However, a ceh-36 loss-offunction mutant (Chang et al 2003) did not reproduce the loss of ASE identity seen upon deletion of the homeodomain binding site (data not shown), indicating a role for other ASEexpressed homeodomain proteins, potentially in combination with CEH-36. In general, homeodomain proteins play an important role in development of the nervous system, that is conserved from C. elegans to mammals (Hobert 2010;Hench et al 2015). Our work now extends this role also to long-term maintenance of cell fate in the face of stochastic fluctuations.…”

Section: Discussionmentioning

confidence: 55%

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

Traets

Burght

Jansen

et al. 2020

Preprint

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Cell fate is maintained over long timescales, yet molecular fluctuations can lead to spontaneous loss of this differentiated state. We uncovered a mechanism that explains lifelong maintenance of ASE neuron fate in C. elegans by the terminal selector transcription factor CHE-1. Fluctuations in CHE-1 level are buffered by the reservoir of CHE-1 bound at its target promoters, which ensure continued che-1 expression by preferentially binding the che-1 promoter. We validated 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. KeywordsNeuronal cell fate, bistability, gene regulatory network, stochastic gene expression, molecular fluctuations, homeodomain proteins, chemotaxis, C. elegans, terminal selector CHE-1, a transcription factor whose expression is transiently induced by the nuclear hormone receptor NHR-67 at the time of determination (Sarin et al. 2009). CHE-1 induces the expression of 500-1000 ASE-specific target genes, such as chemosensory receptors, ion-channels, and neuropeptides, by binding ASE motifs within their promoters (Etchberger et al. 2007). Its continued presence is required for expression of target genes after subtype determination (Etchberger et al. 2009). CHE-1 also upregulates its own expression. This positive feedback loop is necessary for sustaining che-1 expression and ASE cell fate directly after cell determination (Etchberger et al. 2007; Leyva-Diaz and Hobert 2019). Yet, it is unknown whether this positive feedback loop is sufficient for long-term maintenance of ASE fate. The impact of molecular noise, such as variability in CHE-1 protein copy number, on ASE fate maintenance has not been studied. Overall, it is an open question whether a reversible, bistable switch based on positive CHE-1 autoregulation would be sufficiently stable to maintain ASE fate for the animal's lifetime, or if additional mechanisms are necessary to ensure that, once ASE fate is determined, che-1 expression becomes independent of CHE-1 itself and can no longer spontaneously switch off.We show that sufficiently long, transiently induced depletion of CHE-1 caused permanent loss of ASE fate, indicating that it is controlled by a switch that remains reversible long after specification. This raises the question how the switch is protected against molecular noise, which could cause it to spontaneously lose ASE fate. Combining experimental measurements of the key parameters that control the magnitude of noise, i.e. the copy numbers and lifetimes of che-1 mRNA and protein, with stochastic models of the che-1 genetic network, revealed a novel...

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Section: Discussionmentioning

confidence: 55%

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

Traets

Burght

Jansen

et al. 2020

Preprint

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“…This was implemented for the HOX gene egl-5 (Fig. 4), a Polycomb target that is sensitive to lsm-8 ablation, even though its upregulation occurred only in ~45 posterior cells in males (Bender et al, 2004;Hench et al, 2015;Ross and Zarkower, 2003;Soshnikova and Duboule, 2009;Yuzyuk et al, 2009). A similar pattern of egl-5 derepression was scored upon loss of MES-2, the EZH2 homologue, reinforcing the link of LSM2-8 and XRN-2 to Polycomb (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, cell-type specific repression / derepression events are easily masked in RNA-seq datasets of whole animals. In C. elegans, the best conserved HOX cluster repressed by Polycomb includes lin-39 (essential for development of the vulva), ceh-13, mab-5 and egl-5 (HOX5/Scr; HOX1/Lab; HOX6-8/Antp; HOX9-13/Abd-B families, respectively) (Hench et al, 2015). Consistently, worms deficient for MES-2, MES-3 or MES-6 (the PRC2 complex) exhibit ectopic HOX gene expression, albeit in a limited number of cells (Ross and Zarkower, 2003).…”

Section: Cell-specific Hox Gene Up-regulation By Lsm-8 Ablation In Spmentioning

confidence: 99%

LSM2-8 and XRN-2 contribute to the silencing of H3K27me3-marked genes through targeted RNA decay

Mattout

Gaidatzis

Padeken

et al. 2019

Preprint

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SummaryIn fission yeast and plants, RNA-processing pathways contribute to constitutive and facultative heterochromatin silencing, complementing well-characterized pathways of transcriptional repression. However, it was unclear whether this additional level of regulation occurs in metazoans. Here we describe a pathway of silencing in C. elegans somatic cells, in which the highly conserved, RNA binding complex LSM2-8 selectively silences heterochromatic reporters and endogenous genes bearing the Polycomb mark H3K27me3. Importantly, the LSM2-8 complex works cooperatively with XRN-2, a 5’-3’ exoribonuclease, and disruption of the pathway leads to mRNA stabilization. This selective LSM2-8-mediated RNA degradation does not target nor depend on H3K9me2/me3, unlike previously described pathways of heterochromatic RNA degradation. Intriguingly, the loss of LSM2-8 coincides with a localized drop in H3K27me3 levels on lsm-8-sensitive loci only. Together this defines a mechanism of RNA degradation that selectively targets a subset of H3K27me3-marked genes, revealing an unrecognized layer of regulation for facultative heterochromatin in animals.

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“…Little is known about the remaining homeobox genes in C. elegans [83]. Despite having fewer homeobox genes than flies, C. elegans has approximately 25 homeobox genes that do not fall into any of the existing homeobox gene classifications, and are known to be rapidly evolving [84].…”

Section: Of 15mentioning

confidence: 99%

How Weird is The Worm? Evolution of the Developmental Gene Toolkit in Caenorhabditis elegans

Baker

Woollard

2019

JDB

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Comparative developmental biology and comparative genomics are the cornerstones of evolutionary developmental biology. Decades of fruitful research using nematodes have produced detailed accounts of the developmental and genomic variation in the nematode phylum. Evolutionary developmental biologists are now utilising these data as a tool with which to interrogate the evolutionary basis for the similarities and differences observed in Nematoda. Nematodes have often seemed atypical compared to the rest of the animal kingdom—from their totally lineage-dependent mode of embryogenesis to their abandonment of key toolkit genes usually deployed by bilaterians for proper development—worms are notorious rule breakers of the bilaterian handbook. However, exploring the nature of these deviations is providing answers to some of the biggest questions about the evolution of animal development. For example, why is the evolvability of each embryonic stage not the same? Why can evolution sometimes tolerate the loss of genes involved in key developmental events? Lastly, why does natural selection act to radically diverge toolkit genes in number and sequence in certain taxa? In answering these questions, insight is not only being provided about the evolution of nematodes, but of all metazoans.

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The Homeobox Genes of Caenorhabditis elegans and Insights into Their Spatio-Temporal Expression Dynamics during Embryogenesis

Cited by 31 publications

References 96 publications

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

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

LSM2-8 and XRN-2 contribute to the silencing of H3K27me3-marked genes through targeted RNA decay

How Weird is The Worm? Evolution of the Developmental Gene Toolkit in Caenorhabditis elegans

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