Dawes AT et al. (2011) Biophys J "PAR-3 oligomerization may provide an actin-independent mechanism to maintain distinct par protein domains in the early Caenorhabditis elegans embryo."

Munro EM, Dawes AT

[Biophys J, 2011]

Par proteins establish discrete intracellular spatial domains to polarize many different cell types. In the single-cell embryo of the nematode worm Caenorhabditis elegans, the segregation of Par proteins is crucial for proper division and cell fate specification. Actomyosin-based cortical flows drive the initial formation of anterior and posterior Par domains, but cortical actin is not required for the maintenance of these domains. Here we develop a model of interactions between the Par proteins that includes both mutual inhibition and PAR-3 oligomerization. We show that this model gives rise to a bistable switch mechanism, allowing the Par proteins to occupy distinct anterior and posterior domains seen in the early C. elegans embryo, independent of dynamics or asymmetries in the actin cortex. The model predicts a sharp loss of cortical Par protein asymmetries during gradual depletion of the Par protein PAR-6, and we confirm this prediction experimentally. Together, these results suggest both mutual inhibition and PAR-3 oligomerization are sufficient to maintain distinct Par protein domains in the early C. elegans embryo.

Rodin SN et al. (2003) J Mol Evol "Epigenetic silencing may aid evolution by gene duplication."

Riggs AD, Rodin SN

[J Mol Evol, 2003]

Gene duplication is commonly regarded as the main evolutionary path toward the gain of a new function. However, even with gene duplication, there is a loss-versus-gain dilemma: most newly born duplicates degrade to pseudogenes, since degenerative mutations are much more frequent than advantageous ones. Thus, something additional seems to be needed to shift the loss versus gain equilibrium toward functional divergence. We suggest that epigenetic silencing of duplicates might play this role in evolution. This study began when we noticed in a previous publication (Lynch M, Conery JS [2000] Science 291:1151-1155) that the frequency of functional young gene duplicates is higher in organisms that have cytosine methylation (H. sapiens, M. musculus, and A. thaliana) than in organisms that do not have methylated genomes (S. cerevisiae, D. melanogaster, and C. elegans). We find that genome data analysis confirms the likelihood of much more efficient functional divergence of gene duplicates in mammals and plants than in yeast, nematode, and fly. We have also extended the classic model of gene duplication, in which newly duplicated genes have exactly the same expression pattern, to the case when they are epigenetically silenced in a tissue- and/or developmental stage-complementary manner. This exposes each of the duplicates to negative selection, thus protecting from "pseudogenization." Our analysis indicates that this kind of silencing (i) enhances evolution of duplicated genes to new functions, particularly in small populations, (ii) is quite consistent with the subfunctionalization model when degenerative but complementary mutations affect different subfunctions of the gene, and (iii) furthermore, may actually cooperate with the DDC (duplication-degeneration-complementation) process.

Meyer CG et al. (1996) Exp Clin Immunogenet "Met-11 of HLA class II DP alpha 1 first domain associated with onchocerciasis."

Meyer CG, May J, Schnittger L

[Exp Clin Immunogenet, 1996]

Human infection with the pathogenic tissue nematode Onchocerca volvulus may result in a spectrum of clinical manifestations or in a putatively immune condition. A methionine at amino acid position 11 of the HLA class II DP alpha 1 chain correlates with the occurring disease after infection (relative risk 3.3). The alternative alanine at position 11 is, conversely, associated with protection from disease ("relative protection' 3.5). DPA1*0301 is associated with the localized form of disease after O. volvulus infection.

Eric J Aamodt (2005) International Worm Meeting "PAG-3 may be a neuronal cell fate toggle switch"

Eric J Aamodt

[International Worm Meeting, 2005]

PAG-3 is a C2H2 zinc finger transcription factor that is involved in specifying neuronal cell fates and lineages in C. elegans. The pag-3 gene is expressed in numerous embryonic neuroblasts and in the larval ventral nerve cord P-neuroblast sublineages that give rise to the VA, VB and VC neurons. Except in the ventral nerve cord, the cells that express pag-3 also express unc-86, and UNC-86 is required for pag-3::gfp expression in these cells. In the P-neuroblast lineages, on the other hand, pag-3::gfp is expressed even in an unc-86 loss-of-function mutant background and PAG-3 represses unc-86::gfp expression. That is, unc-86::gfp is expressed in the VA, VB and VC neurons in pag-3 mutants. In pag-3 loss-of-function mutants, the BDU neurons adopt a touch receptor neuron fate rather than an interneuron fate. In the BDU neurons, pag-3 is expressed at low levels where it represses mec-3 expression, and in the touch receptor neurons, pag-3 is expressed at high levels where it activates mec-3 expression. The PAG-3 ortholog in Drosophila, Senseless, has a similar role. When Senseless is expressed at low levels, it represses a sensory organ precursor fate and when it is expressed at high levels it activates a sensory organ precursor fate. PAG-3, Senseless and perhaps their mammalian homologs, Gfi-1and Gfi-1B may represent a class of developmental toggle switches that control cell fate decisions by switching from repressors to activators in a concentration dependent manner. PAG-3 will self-associate in vitro at high concentrations so the switch from repressor to activator may occur when these proteins form heterodimers. There is a conserved C-terminal binding protein (CtBP) corepressor-binding site in the zinc finger regions of PAG-3 and Senseless. This region may be masked by self-association because the zinc finger region alone will self-associate. This model predicts that the PAG-3 self-association will occur over a narrow concentration range that is between the concentration of PAG-3 in the BDU nucleus and the concentration of PAG-3 in the ALM nucleus. And it predicts that PAG-3 requires CtBP for its repressor function.

Wamucho A et al. (2023) Int J Mol Sci "Global DNA Adenine Methylation in Caenorhabditis elegans after Multigenerational Exposure to Silver Nanoparticles and Silver Nitrate."

Tsyusko O, May J, Unrine J, Wamucho A

[Int J Mol Sci, 2023]

Multigenerational and transgenerational reproductive toxicity in a model nematode <i>Caenorhabditis elegans</i> has been shown previously after exposure to silver nanoparticles (Ag-NPs) and silver ions (AgNO₃). However, there is a limited understanding on the transfer mechanism of the increased reproductive sensitivity to subsequent generations. This study examines changes in DNA methylation at epigenetic mark N6-methyl-2'-deoxyadenosine (6mdA) after multigenerational exposure of <i>C. elegans</i> to pristine and transformed-via-sulfidation Ag-NPs and AgNO₃. Levels of 6mdA were measured as 6mdA/dA ratios prior to <i>C. elegans</i> exposure (F₀) after two generations of exposure (F₂) and two generations of rescue (F₄) using high-performance liquid chromatography with tandem mass spectrometry (LC-MS/MS). Although both AgNO₃ and Ag-NPs induced multigenerational reproductive toxicity, only AgNO₃ exposure caused a significant increase in global 6mdA levels after exposures (F₂). However, after two generations of rescue (F₄), the 6mdA levels in AgNO₃ treatment returned to F₀ levels, suggesting other epigenetic modifications may be also involved. No significant changes in global DNA methylation levels were observed after exposure to pristine and sulfidized sAg-NPs. This study demonstrates the involvement of an epigenetic mark in AgNO₃ reproductive toxicity and suggests that AgNO₃ and Ag-NPs may have different toxicity mechanisms.

Sturrock M et al. (2015) J R Soc Interface "Protein abundance may regulate sensitivity to external cues in polarized cells."

Dawes AT, Sturrock M

[J R Soc Interface, 2015]

Cell polarization is a ubiquitous process which results in cellular constituents being organized into discrete intracellular spatial domains. It occurs in a variety of cell types, including epithelial cells, immune system cells and neurons. A key player in this process is the Par protein family whose asymmetric localization to anterior and posterior parts of the cell is crucial for proper division and cell fate specification. In this paper, we explore a stochastic analogue of the temporal model of Par protein interactions first developed in Dawes &amp; Munro (Dawes and Munro 2011 Biophys. J. 101, 1412-1422. (doi:10.1016/j.bpj.2011.07.030)). We focus on how protein abundance influences the behaviour of both the deterministic and stochastic versions of the model. In Dawes &amp; Munro (2011), it was found that bistable behaviour in the temporal model of Par protein led to the existence of complementary domains in the corresponding spatio-temporal model. Here, we find that the corresponding temporal stochastic model permits switching behaviour (the model solution 'jumps' between steady states) for lower protein abundances, whereas for higher protein abundances the stochastic and deterministic models are in good agreement (the model solution evolves to one of two steady states). This led us to the testable hypothesis that cells with lower abundances of Par protein may be more sensitive to external cues, whereas cells with higher abundances of Par protein may be less sensitive to external cues. In order to gain more control over the precise abundance of Par protein, we proposed and explored a second model (again, examining both deterministic and stochastic versions) in which the total number of Par molecules is conserved. We found that this model required an additional dimerization reaction in the cytoplasm in order for bistable and switching behaviour to be found. Once this additional reaction was included, we found that both the first and second models gave qualitatively similar results but in different regions of the parameter space, suggesting a further regulatory mechanism that cells could potentially use to modulate their response to external signals.

McGhee JD (1987) Biochemistry "Purification and characterization of a carboxylesterase from the intestine of the nematode Caenorhabditis elegans."

McGhee JD

[Biochemistry, 1987]

The major intestinal esterase from the nematode Caenorhabditis elegans has been purified to essential homogeneity. Starting from whole worms, the overall purification is 9000-fold with a 10% recovery of activity. The esterase is a single polypeptide chain of Mr 60,000 and is stoichiometrically inhibited by organophosphates. Substrate preferences and inhibition patterns classify the enzyme as a carboxylesterase (EC 3.1.1.1), but the physiological function is unknown. The sequence of 13 amino acid residues at the esterase N- terminus has been determined. This partial sequence shows a surprisingly high degree of similarity to the N-terminal sequence of two carboxylesterases recently isolated from Drosophila mojavensis [Pen, J., van Beeumen, J., & Beintema, J. J. (1986) Biochem. J. 238, 691-699].

Wang J et al. (2010) Science "Chromosome size differences may affect meiosis and genome size."

Wang GJ, Keller L, Chen PJ, Wang J

[Science, 2010]

Genetic crosses in many organisms have shown that alleles of unlinked genes generally assort independently of one another during gamete formation. However, variation in chromosome size may affect the process of meiosis and lead to nonindependent assortment of chromosomes. We therefore examined chromosomes with insertions and found that they preferentially segregated away from the X chromosome during meiosis in Caenorhabditis elegans males. Conversely, chromosomes with deletions preferentially segregated with the X chromosome. The degree of segregation bias was significantly associated with the length of the insertion or deletion. Simulations revealed that this segregation bias leads to genome size reduction in hermaphroditic species, a pattern consistent with differences in genome sizes in the genus Caenorhabditis. These results suggest that insertions and deletions may affect chromosome segregation patterns.

Dawes AT et al. (2013) J Theor Biol "Cortical geometry may influence placement of interface between Par protein domains in early Caenorhabditis elegans embryos."

Iron D, Dawes AT

[J Theor Biol, 2013]

During polarization, proteins and other polarity determinants segregate to the opposite ends of the cell (the poles) creating biochemically and dynamically distinct regions. Embryos of the nematode worm Caenorhabditis elegans (C. elegans) polarize shortly after fertilization, creating distinct regions of Par protein family members. These regions are maintained through to first cleavage when the embryo divides along the plane specified by the interface between regions, creating daughter cells with different protein content. In wild type single cell embryos the interface between these Par protein regions is reliably positioned at approximately 60% egg length, however, it is not known what mechanisms are responsible for specifying the position of the interface. In this investigation, we use two mathematical models to investigate the movement and positioning of the interface: a biologically based reaction-diffusion model of Par protein dynamics, and the analytically tractable perturbed Allen-Cahn equation. When we numerically simulate the models on a static 2D domain with constant thickness, both models exhibit a persistently moving interface that specifies the boundary between distinct regions. When we modify the simulation domain geometry, movement halts and the interface is stably positioned where the domain thickness increases. Using asymptotic analysis with the perturbed Allen-Cahn equation, we show that interface movement depends explicitly on domain geometry. Using a combination of analytic and numeric techniques, we demonstrate that domain geometry, a historically overlooked aspect of cellular simulations, may play a significant role in spatial protein patterning during polarization.

Dreyfus DH et al. (1999) Mol Immunol "Comparative analysis of invertebrate Tc6 sequences that resemble the vertebrate V(D)J recombination signal sequences (RSS)."

Gelfand EW, Dreyfus DH

[Mol Immunol, 1999]

Invertebrate cells lack the p53 recombination checkpoint but contain mobile DNA sequences that transpose by a mechanism in part shared with excision of the V(D)J recombination signal sequences (RSS). In this work, inversion, deletion, and duplication of sequences associated with an invertebrate C. elegans Tc6 element is described. The structure of this C. elegans sequence and other dispersed Tc6 elements suggests that covalently closed 'hairpin' structures are not unique to excision of the V(D)J RSS by the RAG proteins, but rather can be generated by transposases at transposon termini leading to characteristic inversion and duplication events. Comparative analysis of recombination events at invertebrate sequences resembling the vertebrate V(D)J RSS may be useful in understanding V(D)J recombination-mediated recombination events in malignant vertebrate cells or genetic diseases such as ataxia telangectasia, in which the p53 recombination checkpoint is defective.