Biology subjects

Stojanovski, K.

Publications and source records attributed to Stojanovski, K..

4 recordsLinked to original sources

bioRxiv2026

The MAPK phosphatase VHP-1 buffers pharynx-to-body proportions against tissue-specific growth imbalance in C. elegans

Maintaining appropriate organ size ratios in the face of growth fluctuations is critical for the development of a reproducible body plan. Yet the mechanisms involved remain poorly understood. Here, we investigated how pharynx-to-body proportions are maintained in Caenorhabditis elegans, combining tissue-specific perturbations, genetic screening, and longitudinal live imaging. A genome-wide RNAi screen revealed that knock-down of the dual-specificity MAPK phosphatase VHP-1 turns animals hypersensitive to inter-tissue growth imbalance caused by pharyngeal or epidermal depletion of the mTORC1 activator RAGA-1 or the ribosomal protein RPL-22. In contrast, vhp-1 mutants tolerated global raga-1 loss, indicating a specific requirement for vhp-1 under tissue growth imbalance. Knock-down of the p38 pathway suppressed the imbalance-specific defects of vhp-1 mutants. In contrast, JNK knock-down effectively rescued the pleiotropic phenotypes of vhp-1 mutants but only weakly reduced their sensitivity to RAGA-1 imbalance, indicating that these two stress-MAPK pathways make distinct contributions to the response to growth imbalance. Finally, whole-animal VHP-1 levels increased upon epidermal RAGA-1 depletion, and epidermal VHP-1 depletion did not reproduce the sensitivity caused by global vhp-1 loss, consistent with a contribution from VHP-1 outside the growth-perturbed epidermis in buffering against local growth imbalance.

developmental biology↗

bioRxiv2025

Intergenerational control of ribosomes under dietary restriction

Cells adjust their proteome to their environment. Most prominently, ribosome expression scales near linearly with the cellular growth rate to provide sufficient translational capacity while preventing metabolically wasteful ribosomal excess. In microbes, such proteome adjustments can passively perpetuate through symmetric cell division. However, in animals, a passive propagation is hindered by the separation between soma and germline. This separation raises the crucial question whether the proteome of animals is reset at every generation or can be propagated from parent to offspring despite this barrier. We addressed this question by exploring the intergenerational effects of dietary restriction in C. elegans, combining proteomics and live imaging. While most proteins showed no intergenerational regulation, ribosomal proteins remained reduced in offspring after maternal dietary restriction. When offspring of dietarily restricted mothers were raised under improved dietary conditions, this reduced ribosome content delayed their growth until normal ribosomal protein levels were restored. Soma-specific maternal inhibition of mTORC1 signalling replicated these effects, while other growth-reducing perturbations, such as reduced insulin signalling or maternal ribosome depletion, did not impact offspring ribosomes. Thus, mTORC1 signalling bridges across the soma-germline divide to regulate ribosome levels of the next generation, likely priming the offspring for the anticipated demand in protein synthesis.

physiology↗

bioRxiv2023

Cohesin forms fountains at active enhancers in C. elegans

Transcriptional enhancers must locate their target genes with both precision and efficiency. In mammals, this specificity is facilitated by topologically associated domains (TADs), which restrict the enhancer search space through three-dimensional genome organization. In contrast, the nematode genome lacks such TAD-based segmentation despite harboring over 30000 sequences with chromatin signature characteristic of enhancers, thereby raising the question of how enhancer-promoter specificity is achieved. Using high-resolution Hi-C in C. elegans, we identify distinct 3D chromatin structures surrounding active enhancers, which we term fountains. These structures span 38 kb in average, are unique to active enhancers, and are enriched for the major somatic cohesin complex. Fountains collapse upon in vivo cohesin cleavage, indicating their cohesin dependency. Notably, fountains accumulate topological stress, as evidenced by the enrichment of topoisomerases and the psoralen-binding signature of negatively-supercoiled DNA. Functionally, fountain disassembly correlates with transcriptional upregulation of active enhancer-proximal genes, suggesting that fountains act as spatial repressors of enhancer activity. This repression is particularly pronounced for neuronal genes, including the skn-1/Nrf gene, which becomes upregulated, switches isoform and transcription start site upon cohesin loss in a pair of head neurons. Behaviorally, cohesin cleavage alters nematode movement and foraging behavior, linking enhancer-driven transcriptional changes to neural circuit function and organismal phenotypes, reminiscent of pathologies caused by cohesin mutations in humans. Together, our findings uncover fountains as a novel 3D chromatin feature that modulates enhancer activity in a TAD-less genome, establishing a mechanistic link between genome architecture, gene regulation and behavior.

genomics↗

bioRxiv2022

Ultra-sensitive coupling between organ growth and size by YAP-1 ensures uniform body plan proportions in C. elegans

Imbalance between the growth rate of different organs can amplify to large deviations of their size proportions during development. We show that, for the C. elegans pharynx, such size divergence is prevented by reciprocal coordination of pharyngeal growth with other tissues. Live imaging of hundreds of individuals revealed that small pharynxes grow more rapidly than large pharynxes, catching up in volume during development. Moreover, pharynx-to-body size proportions were robust to even strong tissue-specific inhibition of mTORC1 and insulin signalling. Tissue-specific depletion of these pathways slowed-down the growth of the respective tissue and additionally triggered a systemic growth response that ensured appropriate organ size proportions. By mathematical modelling, we show that the conservation of proportions requires a bi-directional ultra-sensitive coupling of body growth and pharynx size that cannot be explained by a reduction of food uptake alone. Instead, organ growth coordination requires regulation by the mechano-transducing transcriptional co-activator YAP/yap-1. Knock-down of yap-1 makes animals sensitive to tissue-specific inhibition mTORC1 inhibition, causing a disproportionate pharynx and developmental arrest. Our data suggests that mechano-transduction tightly coordinates organ growth during C. elegans development to ensure the uniformity of body plan proportions among individuals.

developmental biology↗