Developmental phenomics suggests that H3K4 monomethylation confers multi-level phenotypic robustness

Gándara, Lautaro; Tsai, Albert; Ekelöf, Måns; Galupa, Rafael; Noon, Ella Preger-Ben; Alexandrov, Theodore; Crocker, Justin

doi:10.1016/j.celrep.2022.111832

Cited by 7 publications

(6 citation statements)

References 53 publications

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“…These results show that perturbation of one node of the developmental network, the bicoid dosage, can lead to profound organism-wide responses across multiple phenotypic scales. Importantly, these observations highlight the deep connections between multiple phenotypic layers of multicellular systems and argue for a broader 'phenomics' perspective 16 , instead of a strictly gene-centric view. Exploring the interplay of metabolic and developmental networks could transform our understanding of evolution and development across variable ecologies 5,15 , as such processes are fundamentally linked 67 .…”

Section: Discussionmentioning

confidence: 93%

“…Thousands of individual genes may contribute to phenotypes through expression in relevant cells 10 , and the contributions of each genetic variant to developmental fates are often small and challenging to measure [11][12][13] . Therefore, it is essential to consider regulatory evolution and development both at the systems level and across populations [14][15][16] . Clearly, approaches to elicit the relationships between different phenotypic layers and how these changes manifest across populations are needed to understand the evolution of developmental regulatory networks.…”

Section: Introductionmentioning

confidence: 99%

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Rapid response of fly populations to gene dosage across development and generations

Li¹,

Gándara²,

Ekelof³

et al. 2022

Preprint

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It remains unknown how developmental systems evolve in response to variable genetic and environmental conditions. Here, we have examined the evolvability of the classic bicoid network in Drosophila, which is essential for anterior-posterior patterning in the early embryo. This network can be synthetically perturbed by increasing the dosage of bicoid, which causes a posterior shift of the network's regulatory outputs and a decrease in fitness. To directly monitor network evolution across populations with extra copies of bicoid, we performed genome-wide EMS mutagenesis, followed by experimental evolution. After only 8-15 generations, evolved populations have normalized patterns of gene expression and increased survival. Using a phenomics approach, we find that populations normalized through rapid increases in embryo size driven by maternal changes in metabolism and ovariole development. We extend our results to wild populations of flies, demonstrating strong predictability. Together, our results necessitate a broader view of regulatory network evolution at the systems level. This study highlights the power of synthetic evolution using animal systems, a generalizable platform for the dissection of gene regulation and complex genomes.

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Rapid response of fly populations to gene dosage across development and generations

Li¹,

Gándara²,

Ekelof³

et al. 2022

Preprint

Self Cite

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“…Here, building upon our previous attempts at deep phenotyping 36 , we developed a high-throughput phenotyping platform, which enabled us to characterize the behavioral effects of more than 1,000 agrochemicals when employed at varying concentrations. Strikingly, we found that 57% of the agrochemicals in our library exert significant effects on the behavior of Drosophila larvae when exposed for a short time period at sublethal concentrations (Fig.…”

Section: Discussionmentioning

confidence: 99%

Pervasive sublethal effects of agrochemicals as contributing factors to insect decline

Gandara,

Jacoby,

Laurent

et al. 2024

Preprint

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Insect biomass is declining across the globe at an alarming rate. Climate change and the widespread use of pesticides have been hypothesized as two underlying drivers. However, the lack of systematic experimental studies across chemicals and species limits our causal understanding of this problem. Here, we employed a chemical library encompassing 1024 different molecules (including insecticides, herbicides, fungicides, and plant growth inhibitors) to investigate how insect populations are affected by varying concentrations of pesticides, focusing on sublethal doses. Using a controlled laboratory pipeline for Drosophila melanogaster, we found that 57% of these chemicals affect the behavior of larvae at sublethal concentrations, and an even higher proportion compromises long-term survivability after acute exposure. Consistent with these results, we observed that exposure to chemicals at doses orders of magnitude below lethality induced widespread phosphorylation changes across the larval proteome. The effects of agrochemicals were amplified when the ambient temperature was increased by four degrees. We also tested the synergistic effects of multiple chemicals at doses found widely in nature and observed fitness-reducing changes in larval developmental time, behavior, and reproduction. Finally, we expanded our investigation to additional fly species, mosquitos, and butterflies and detected similar behavioral alterations triggered by pesticides at sublethal concentrations. Our results provide experimental evidence that strongly suggests sublethal doses of agrochemicals coupled with changes in environmental temperatures are contributing to the global decline in insect populations. We anticipate that our assays can contribute to improving chemical safety assessment, better protect the environment, secure food supplies, and safeguard animal and human health, as well as understand our rapidly changing world.

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“…These fine-tuning mechanisms are redundant and produce only mild mutant phenotypes. Nevertheless, they might be essential for robust embryonic development under suboptimal conditions ( 49 ).…”

Section: Discussionmentioning

confidence: 99%

Cereblon influences the timing of muscle differentiation in Ciona tadpoles

Long,

Mariossi,

Cao

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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Thalidomide has a dark history as a teratogen, but in recent years, its derivates have been shown to function as potent chemotherapeutic agents. These drugs bind cereblon (CRBN), the substrate receptor of an E3 ubiquitin ligase complex, and modify its degradation targets. Despite these insights, remarkably little is known about the normal function of cereblon in development. Here, we employ Ciona , a simple invertebrate chordate, to identify endogenous Crbn targets. In Ciona, Crbn is specifically expressed in developing muscles during tail elongation before they acquire contractile activity. Crbn expression is activated by Mrf, the ortholog of MYOD1, a transcription factor important for muscle differentiation. CRISPR/Cas9-mediated mutations of Crbn lead to precocious onset of muscle contractions. By contrast, overexpression of Crbn delays contractions and is associated with decreased expression of contractile protein genes such as troponin. This reduction is possibly due to reduced Mrf protein levels without altering Mrf mRNA levels. Our findings suggest that Mrf and Crbn form a negative feedback loop to control the precision of muscle differentiation during tail elongation.

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Developmental phenomics suggests that H3K4 monomethylation confers multi-level phenotypic robustness

Cited by 7 publications

References 53 publications

Rapid response of fly populations to gene dosage across development and generations

Rapid response of fly populations to gene dosage across development and generations

Pervasive sublethal effects of agrochemicals as contributing factors to insect decline

Cereblon influences the timing of muscle differentiation in Ciona tadpoles

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