Biology subjects

Ben-David, E.

Publications and source records attributed to Ben-David, E..

10 recordsLinked to original sources

bioRxiv2025

Dissecting regulatory syntax in human development with scalable multiomics and deep learning

Transcription factors (TFs) establish cell identity during development by binding regulatory DNA in a sequence-specific manner, often promoting local chromatin accessibility, and regulating gene expression. Mapping accessible chromatin offers critical insights into transcriptional control, but available datasets for human development are restricted to bulk tissue, single organs, or single modalities. Here, we present the Human Development Multiomic Atlas (HDMA), a single-cell atlas of chromatin accessibility and gene expression from 817,740 fetal cells across 12 organs, spanning 203 cell types and over 1 million candidate cis-regulatory elements, many of which exhibit organ-specific in vivo enhancer activity. Deep learning models trained to predict accessibility from local DNA sequence unravel a comprehensive lexicon of motifs which influence accessibility, including composite motifs exhibiting distinct syntactic constraints predicted to mediate TF cooperativity. We identify "hard" syntactic rules requiring precise motif spacing and orientation, "soft" rules allowing flexible motif arrangements, and ubiquitous motifs that inhibit accessibility. Model-based interpretation of genetic variants reveals that disruption of motifs with positive and negative effects is associated with concordant effects on gene expression. Our work delineates how motif syntax governs cell type-specific chromatin accessibility and provides a foundational resource for decoding cis-regulatory logic and interpreting genetic variation during human development.

genomics↗

bioRxiv2024

Molecular patterns of evolutionary changes throughout the whole nervous system of multiple nematode species

One avenue to better understand brain evolution is to map molecular patterns of evolutionary changes in neuronal cell types across entire nervous systems of distantly related species. Generating whole-animal single-cell transcriptomes of three nematode species from the Caenorhabditis genus, we observed a remarkable stability of neuronal cell type identities over more than 45 million years of evolution. Conserved patterns of combinatorial expression of homeodomain transcription factors are among the best classifiers of homologous neuron classes. Unexpectedly, we discover an extensive divergence in neuronal signaling pathways. While identities of neurotransmitter-producing neurons (glutamate, acetylcholine, GABA and several monoamines) remain stable, ionotropic and metabotropic receptors for all these neurotransmitter systems show substantial divergence, resulting in more than half of all neuron classes changing their capacity to be receptive to specific neurotransmitters. Neuropeptidergic signaling is also remarkably divergent, both at the level of neuropeptide expression and receptor expression, yet the overall dense network topology of the wireless neuropeptidergic connectome remains stable. Novel neuronal signaling pathways are suggested by our discovery of small secreted proteins that show no obvious hallmarks of conventional neuropeptides, but show similar patterns of highly neuron-type-specific and highly evolvable expression profiles. In conclusion, by investigating the evolution of entire nervous systems at the resolution of single neuron classes, we uncover patterns that may reflect basic principles governing evolutionary novelty in neuronal circuits.

evolutionary biology↗

bioRxiv2024

A regulatory module driving the recurrent evolution of irreducible molecular complexes.

To sustain life, molecular complexes require the concerted action of multiple proteins, each relying on one another to perform intricate tasks. However, how such interdependent protein interactions evolve in the first place is poorly understood. To address this, we investigated the origins of a group of fast-evolving genetic parasites--toxin-antidote elements--which boil down this dilemma to a simple question: what came first, the toxin or the antidote? By integrating quantitative genetics, biochemistry, and evolutionary genomics, we discovered that toxins and antidotes can arise simultaneously through the duplication of a regulatory module comprising an F-box protein in linkage to its substrate. Our findings provide one solution to the recurrent emergence of mutual dependence in protein complexes and illustrate in detail how complexity can swiftly arise from simplicity.

genomics↗

bioRxiv2023

Pumping Iron: A Multi-omics Analysis of Two Extremophilic Algae Reveals Mechanisms of Iron Economy

Marine algae are responsible for half of the worlds primary productivity, but this critical carbon sink is often constrained by insufficient iron. One species of marine algae, Dunaliella tertiolecta, is remarkable for its ability to maintain photosynthesis and thrive in low-iron environments. A related species, Dunaliella salina Bardawil, shares this attribute but is an extremophile found in hyper-saline environments. To elucidate how algae manage their iron requirements, we produced high-quality genome assemblies and transcriptomes for both species to serve as a foundation for a comparative multi-omics analysis. We identified a host of iron-uptake proteins in both species, including a massive expansion of transferrins and a novel family of siderophore-iron uptake proteins. Complementing these multiple iron-uptake routes, ferredoxin functions as a large iron reservoir that can be released by induction of flavodoxin. Proteomic analysis revealed reduced investment in the photosynthetic apparatus coupled with remodeling of antenna proteins by dramatic iron-deficiency induction of TIDI1, an LHCA-related protein found also in other chlorophytes. These combinatorial iron scavenging and sparing strategies make Dunaliella unique among photosynthetic organisms. Significance StatementDespite their small size, microalgae play a huge role in CO2 uptake via photosynthesis, and represent an important target for climate crisis mitigation efforts. Most photosynthesis proteins require iron as a co-factor so that insufficient iron often limits algal CO2 sequestration. With this in mind, we examined a genus of microalgae called Dunaliella that is exceptionally well-adapted to low iron environments. We produced complete genomes, transcriptomes, and proteomes for two species of Dunaliella that hail from radically different environments: one from coastal ocean waters and the other from salt flats. We identified dozens of genes and multiple, complementary strategies that both species utilize for iron-uptake and management that explain Dunaliellas remarkable ability to thrive on low iron.

systems biology↗

bioRxiv2022

The evolution of an RNA-based memory of self in the face of genomic conflict

Distinguishing endogenous genes from selfish ones is essential for germline integrity. In animals, small regulatory RNAs play a central role in this process; however, the underlying principles are largely unknown. To fill this gap, we studied how selfish toxin-antidote elements (TAs) evade silencing in the nematode Caenorhabditis tropicalis. We found that the slow-1/grow-1 TA is active only when maternally inherited. Surprisingly, this parent-of-origin effect stems from a regulatory role of the toxins mRNA: maternal slow-1 mRNA--but not SLOW-1 protein--licenses slow-1 expression in the zygote by counteracting piRNAs. Our results indicate that epigenetic licensing-- known to play a role in C. elegans sex-determination--is likely a common mechanism that hinders the spread of selfish genes in wild populations while ensuring a lasting memory of self in the germline.

genetics↗

bioRxiv2022

Uncovering molecular iron compounds in the living human brain.

Strict iron regulation is essential for normal brain function. The iron homeostasis, determined by the milieu of available iron compounds, is impaired in aging, neurodegenerative diseases and cancer. However, non-invasive assessment of different molecular iron environments implicating brain tissues iron homeostasis remains a challenge. We present a novel magnetic resonance imaging (MRI) technology sensitive to the iron homeostasis of the living brain (the r1-r2* relaxivity). In vitro, our MRI approach reveals the distinct paramagnetic properties of ferritin, transferrin and ferrous iron. In the in vivo human brain, we validate our approach against ex vivo iron compounds quantification and gene expression. Our approach varies with the iron mobilization capacity across brain regions and in aging. It reveals brain tumors iron homeostasis, and enhances the distinction between tumor tissue and non-pathological tissue without contrast agents. Therefore, our approach may allow for non-invasive research and diagnosis of iron homeostasis in living human brains. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=133 SRC="FIGDIR/small/490254v2_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@17e2722org.highwire.dtl.DTLVardef@13b646aorg.highwire.dtl.DTLVardef@3d9bfeorg.highwire.dtl.DTLVardef@cc5b7d_HPS_FORMAT_FIGEXP M_FIG Non-invasive assessment of normal and impaired iron homeostasis in living human brains. C_FIG

neuroscience↗

bioRxiv2020

Whole-organism mapping of the genetics of gene expression at cellular resolution

Genetic regulation of gene expression underlies variation in disease risk and other complex traits. The effect of expression quantitative trait loci (eQTLs) varies across cell types; however, the complexity of mammalian tissues makes studying cell-type eQTLs highly challenging. We developed a novel approach in the model nematode Caenorhabditis elegans that uses single cell RNA sequencing to map eQTLs at cellular resolution in a single one-pot experiment. We mapped eQTLs across cell types in an extremely large population of genetically distinct C. elegnas individuals. We found cell-type-specific trans-eQTL hotspots that affect the expression of core pathways in the relevant cell types. Finally, we found single-cell-specific eQTL effects in the nervous system, including an eQTL with opposite effects in two individual neurons. Our results show that eQTL effects can be specific down to the level of single cells.

genetics↗

bioRxiv2020

Ubiquitous selfish toxin-antidote elements in Caenorhabditis species

Toxin-antidote elements (TAs) are selfish genetic dyads that spread in populations by selectively killing non-carriers. TAs are common in prokaryotes, but few examples are known in animals. We discovered five maternal-effect TAs in the nematode Caenorhabditis tropicalis and one in C. briggsae. Unlike previously reported TAs, five of these novel toxins do not kill embryos but instead cause larval arrest or developmental delay. We identified the genes underlying a TA causing developmental delay, slow-1/grow-1, and found that the toxin, slow-1, is homologous to nuclear hormone receptors. Last, we found that balancing selection of conflicting TAs hampers their ability to drive in populations, leading to more stable genetic incompatibilities. Our results show that TAs are common in Caenorhabditis species, target a wide range of developmental processes, and may act as barriers preventing gene flow.

genomics↗

bioRxiv2018

Fast genetic mapping of complex traits in C. elegans using millions of individuals in bulk

Genetic studies of complex traits in animals have been hindered by the need to generate, maintain, and phenotype large panels of recombinant lines. We developed a new method, C. elegans eXtreme Quantitative Trait Locus (ceX-QTL) mapping, that overcomes this obstacle via bulk selection on millions of unique recombinant individuals. We used ceX-QTL to map a drug resistance locus with high resolution. We also mapped differences in gene expression in live worms and discovered a regulatory feedback loop that responds to changes in HSP-90 chaperone activity. Lastly, we used ceX-QTL to map loci that influence fitness and discovered that one such locus is caused by a deletion in a highly conserved chromatin reader in the N2 reference strain. ceX-QTL is fast, powerful and cost-effective, and will accelerate the study of complex traits in animals.

genetics↗

bioRxiv2017

A maternal-effect genetic incompatibility in Caenorhabditis elegans

Selfish genetic elements spread in natural populations and have an important role in genome evolution. We discovered a selfish element causing a genetic incompatibility between strains of the nematode Caenorhabditis elegans. The element is made up of sup-35, a maternal-effect toxin that kills developing embryos, and pha-1, its zygotically expressed antidote. pha-1 has long been considered essential for pharynx development based on its mutant phenotype, but this phenotype in fact arises from a loss of suppression of sup-35 toxicity. Inactive copies of the sup-35/pha-1 element show high sequence divergence from active copies, and phylogenetic reconstruction suggests that they represent ancestral stages in the evolution of the element. Our results suggest that other essential genes identified by genetic screens may turn out to be components of selfish elements.

evolutionary biology↗