Biology subjects

Mor, Y.

Publications and source records attributed to Mor, Y..

6 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↗

bioRxiv2024

Perception of Temperature Even in the Absence of Actual Change is Sufficient to Drive Transgenerational Epigenetic Inheritance

Can processes occurring in one individuals nervous system influence the physiology of the descendants? Here, we explored the hypothesis that parents sensation or perception of environmental cues can influence their offspring, extending across many subsequent generations. We show that in Caenorhabditis elegans, temperature perception by the AFD thermosensory neurons initiates a signaling cascade that, directly or indirectly, induces transgenerational changes in RNAi factors, small RNAs, and their target genes. Moreover, we identify secreted factors that enable this neuron-to-germline communication and trace the path of the epigenetic signal. We further model the process mathematically, and the model yields new predictions that we validate experimentally: blocking sensory input dampens RNAi inheritance initiated by exogenous double-stranded RNA (dsRNA). Together, our results demonstrate that sensory perception is sufficient to influence small RNA-mediated heritable gene expression memory.

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↗

bioRxiv2020

Coronacept - a potent immunoadhesin against SARS-CoV-2

Angiotensin-converting enzyme 2 (ACE2) is the cellular receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Computational analysis of mammalian ACE2 orthologues suggests various residues at the interface with the viral receptor binding domain that could facilitate tighter interaction compared to the human-ACE2. Introducing several mutations to the human-ACE2 resulted with significantly augmented affinity to the viral spike complex. This modified human-ACE2 fused to an Fc portion of an antibody makes a potent immunoadhesin that effectively targets SARS-CoV-2.

bioengineering↗

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↗

bioRxiv2017

WorMachine: Machine Learning-Based Phenotypic Analysis Tool for Worms

While Caenorhabditis elegans nematodes are powerful model organisms, quantification of visible phenotypes is still often labor-intensive, biased, and error-prone. We developed \"WorMachine\", a three-step MATLAB-based image analysis software that allows automated identification of C. elegans worms, extraction of morphological features, and quantification of fluorescent signals. The program offers machine learning techniques which should aid in studying a large variety of research questions. We demonstrate the power of WorMachine using five separate assays: scoring binary and continuous sexual phenotypes, quantifying the effects of different RNAi treatments, and measuring intercellular protein aggregation. Thus, WorMachine is a \"quick and easy\", high-throughput, automated, and unbiased analysis tool for measuring phenotypes.

bioinformatics↗