Biology subjects

Lev, I.

Publications and source records attributed to Lev, I..

9 recordsLinked to original sources

bioRxiv2026

Scavenger Cells Failure to Maintain Systemic RNA Homeostasis Causes Epigenetically Inherited Germline Tumors

Temporary disruptions to epigenetic mechanisms can misroute development and permanently alter cell fate. In particular, it was recently shown that transient loss of Polycomb silencing in flies irreversibly reprograms cells toward cancer (Parreno et al. 2024). Whether somatic dysfunction in parents can create multi-generational heritable susceptibility to tumorigenesis is unknown. In eutelic organisms like Caenorhabditis elegans, adult somatic cells no longer divide, precluding somatic cancer, yet tumors can still form in the continuously dividing germline. Here, we show that disruption of coelomocytes, somatic scavenger cells, just in C. elegans mothers, provokes transgenerationally heritable germline tumorigenesis that persists for multiple generations in genetically wild-type descendants. We found that when the coelomocytes phagocytic activity dysfunctions, it impairs clear out of RNA from body fluids, and thus disrupts systemic RNA homeostasis, allowing excess somatic RNAs to access the germline, and leading to widespread transcriptional and small RNA dysregulation and transgenerational loss of germline identity. Converging lines of evidence point towards small RNAs being the heritable agents carrying the pathological information. Together, these findings highlight mechanisms which maintain systemic RNA homeostasis as an important protective barrier against heritable tumorigenesis.

genetics↗

bioRxiv2025

BarlowTrack: A Self-Supervised Framework for Zero-Shot Multi-Object Cell Tracking

Recent advances in neuroscience have made it possible to image large brain regions at single-cell resolution. However, classic methods for processing these videos into neuronal time series fail in the presence of large and nonrigid deformations, in particular for freely moving animals. Several successful algorithms have been proposed to solve this problem in moving C. elegans, but they are highly specific to the conditions of a single research setting. We propose a tracking pipeline based on self-supervised learning that achieves a high level of zero-shot accuracy across conditions, and, for the first time, independent laboratories. We contribute a novel term in the Barlow Twins loss function to encourage decorrelation of features across detected instances at the same time point. To encourage broad adoption, we use the standardized Neurodata Without Borders (NWB) format and we provide a GUI for visualization of the final results and neuronal time series. Finally, we provide a benchmark of datasets with ground truth annotations in the NWB format for further algorithmic development.

bioinformatics↗

bioRxiv2025

An intrinsic neuronal manifold underlies brain-wide hierarchical organization of behavior in C. elegans

Large-scale neuronal recordings in various species have revealed behavior-related activity patterns. Surprisingly, these activities are distributed across brain regions, including sensory areas. However, their origins and functions are incompletely understood. Using whole-brain imaging in freely behaving C. elegans, we discover that such distributed brain activity is dominated by a low dimensional manifold, corresponding to the major action sequence of C. elegans. The manifold originates largely from intrinsic dynamics, with minor contributions from movement-induced sensations. We discover a new function of the manifold: to gate the activity of a large number of neuron classes. This gating constrains them to selectively encode faster time-scale motor patterns during specific brain states. We therefore propose that one principle function of brain-wide dynamics is to enable hierarchical organization of behavior: information about major actions is broadcast via a distributed manifold, to enable nesting of granular motor patterns within those major actions.

neuroscience↗

bioRxiv2023

Nucleus-Independent Transgenerational Small RNA Inheritance in C. elegans

Studies using C. elegans nematodes demonstrated that, against the dogma, animals can transmit epigenetic information transgenerationally. While it is now clear that in these worms ancestral RNA interference (RNAi) responses continue to regulate gene expression for many generations, it is still debated whether the primary agent that perpetuates heritable silencing is RNA or chromatin, and whether the information is communicated to the next generation inside or outside of the nucleus. Here we take advantage of the tractability of gene-specific double stranded RNA-induced heritable silencing to answer these questions. We demonstrate that RNAi can be inherited independently of any changes to the chromatin or any other nuclear factors via mothers that are genetically engineered to transmit only their ooplasm but not the oocytes nuclei to the next generation. Nucleus-independent RNA inheritance depends on ZNFX-1, an RNA-binding germ granule resident protein. We find that upon manipulation of normal germ granules functions (in pptr-1 mutants) nucleus-independent RNA inheritance becomes stronger, and can occur even in znfx-1 mutants. Utilizing RNA sequencing, chimeric worms, and sequence polymorphism between different C. elegans isolates, we identify endogenous small RNAs which, similarly to exogenous siRNAs, are inherited in a nucleus-independent manner. From an historical perspective, nucleus-independent inheritance of small RNAs might be regarded as partial vindication of discredited cytoplasmic inheritance theories from the 19th century, such as Darwins "pangenesis" theory.

genetics↗

bioRxiv2020

Heritable Sexual Attraction under Parental Control

It is unknown whether transient transgenerational epigenetic responses to environmental challenges affect the process of evolution, which typically unfolds over many generations. Here we show that in C. elegans, inherited small RNAs shape the hard-wired genome and control genetic variation by regulating the decision of whether to self-fertilize or outcross. We found that under stressful temperatures younger hermaphrodites secrete a male-attracting pheromone. Attractiveness transmits transgenerationally to unstressed progeny via heritable small RNAs and the Argonaute Heritable-RNAi-Deficient-1. We identified an endogenous small interfering RNA pathway, enriched in endo-siRNAs which target sperm genes, that transgenerationally regulates sexual attraction, male prevalence, and outcrossing rates. Multigenerational mating competitions and mathematical simulations revealed that over generations, animals that inherit attractiveness mate more, and their alleles spread in the population. We propose that sperm serves as a "stress sensor" which, via small RNA inheritance, can promote outcrossing in challenging environments, when increasing genetic variation is advantageous.

molecular biology↗

bioRxiv2019

Germ Granules Functions are Memorized by Transgenerationally Inherited Small RNAs

In C. elegans nematodes, components of liquid-like germ granules were shown to be required for transgenerational small RNA inheritance. Surprisingly, we show here that mutants with defective germ granules (pptr-1, meg-3/4, pgl-1) can nevertheless inherit potent small RNA-based silencing responses, but some of the mutants lose this ability after many generations of homozygosity. Animals mutated in pptr-1, which is required for stabilization of P granules in the early embryo, display extremely strong heritable RNAi responses, which last for tens of generations, long after the responses in wild type animals peter out. The phenotype of mutants defective in the core germ granules proteins MEG-3 and MEG-4, depends on the genotype of the ancestors: Mutants that derive from maternal lineages that had functional MEG-3 and MEG-4 proteins exhibit enhanced RNAi inheritance for multiple generations. While functional ancestral meg-3/4 alleles correct, and even potentiates the ability of mutant descendants to inherit RNAi, defects in germ granules functions can be memorized as well; Wild type descendants that derive from lineages of mutants show impaired RNAi inheritance for many (>16) generations, although their germ granules are intact. Importantly, while P granules are maternally deposited, wild type progeny derived from meg-3/4 male mutants also show reduced RNAi inheritance. Unlike germ granules, small RNAs are inherited also from the sperm. Moreover, we find that the transgenerational effects that depend on the ancestral germ granules require the argonaute protein HRDE-1, which carries heritable small RNAs in the germline. Indeed, small RNA sequencing reveals imbalanced levels of many endogenous small RNAs in germ granules mutants. Strikingly, we find that hrde-1;meg-3/4 triple mutants inherit RNAi, although hrde-1 was previously thought to be essential for heritable silencing. We propose that germ granules sort and shape the RNA pool, and that small RNA inheritance memorizes this activity for multiple generations.

genetics↗

bioRxiv2018

Insights from Bacillus anthracis strains isolated from permafrost in the tundra zone of Russia

This article describes Bacillus anthracis strains isolated during an outbreak of anthrax on the Yamal Peninsula in the summer of 2016 and independently in Yakutia in 2015. A common feature of these strains is their conservation in permafrost, from which they were extracted either due to the thawing of permafrost (Yamal strains) or as the result of paleontological excavations (Yakut strains). All strains isolated on the Yamal share an identical genotype belonging to lineage B.Br.001/002, pointing to a common source of infection in a territory over 250 km in length. In contrast, during the excavations in Yakutia, three genetically different strains were recovered from a single pit. One strain belongs to B.Br.001/002, as the Yamal strains. Despite the remoteness of Yamal from Yakutia, whole genome sequence analysis showed that the B.Br.001/002 strains are very closely related. The two other strains contribute to two different branches of A.Br.008/011, one of the remarkable polytomies described so far in B. anthracis population. The geographic distribution of the strains belonging to this polytomy is suggesting that this polytomy emerged in the thirteenth century, in combination with the constitution of a unified Mongol empire extending from China to Eastern Europe. We propose an evolutionary model for B. anthracis recent evolution in which the B lineage spread throughout Eurasia and was subsequently replaced by the A lineage except in some geographically isolated areas.

microbiology↗

bioRxiv2018

Inter-generational Consequences for Growing C. elegans in Liquid

In recent years, studies in Caenorhabditis elegans nematodes have shown that different stresses can generate multigenerational changes. Here we show that worms that grow in liquid media, and also their plate-grown progeny, are different from worms whose ancestors were grown on plates. It has been suggested that C.elegans might encounter liquid environments in nature, although actual observations in the wild are few and far between. In contrast, in the lab, growing worms in liquid is commonplace, and often used as an alternative to growing worms on agar plates, to control the composition of the worms diet, to starve (and synchronize) worms, or to grow large populations for biochemical assays. We found that plate-grown descendants of M9 liquid media-grown worms were longer than control worms, and the heritable effects were apparent already very early in development. We tested for the involvement of different known epigenetic inheritance mechanisms, but could not find a single mutant in which these intergenerational effects are canceled. While we found that growing in liquid always leads to inter-generational changes in the worms size, trans-generational effects were found to be variable, and in some cases the effects were gone after 1 -2 generations. These results demonstrate that standard cultivation conditions in early life can dramatically change the worms physiology in adulthood, and can also affect the next generations.

genetics↗

bioRxiv2018

H3K9me3 is Required for Transgenerational Inheritance of Small RNAs that Target a Unique Subset of Newly Evolved Genes

In Caenorhabditis elegans, RNA interference (RNAi) responses can transmit across generations via small RNAs. RNAi inheritance is associated with Histone-3-Lysine-9 tri-methylation (H3K9me3) of the targeted genes. In other organisms, maintenance of silencing requires a feed-forward loop between H3K9me3 and small RNAs. Here we show that in C. elegans not only is H3K9me3 unnecessary for inheritance, the modifications function depends on the identity of the RNAi-targeted gene. We found an asymmetry in the requirement for H3K9me3 and the main worm H3K9me3 methyltransferases, SET-25 and SET-32. Both methyltransferases promote heritable silencing of the foreign gene gfp, but are dispensable for silencing of the endogenous gene oma-1. Genome-wide examination of heritable endogenous small interfering RNAs (endo-siRNAs) revealed that the SET-25-dependent heritable endo-siRNAs target newly acquired and highly H3K9me3 marked genes. Thus, \"repressive\" chromatin marks could be important specifically for heritable silencing of genes which are flagged as \"foreign\", such as gfp.

genetics↗