Biology subjects

Gavriouchkina, D.

Publications and source records attributed to Gavriouchkina, D..

11 recordsLinked to original sources

bioRxiv2026

Parental care is a genetic capacitor

Parental care is widespread across the animal kingdom and plays a critical role in offspring development. Yet, its broader genetic and evolutionary impacts remain underexplored. Here, using the biparental burying beetle Nicrophorus vespilloides as a model, we show that parental care acts as a genetic capacitor: it allows genetic variation to accumulate while care is present and releases it when care is disrupted. By experimentally manipulating care, we demonstrate that parental care suppresses genetic variation associated with offspring body size, which is released when care is lost. To investigate the underlying molecular mechanisms, we generate a chromosome-scale genome assembly for N. vespilloides, alongside a single-nucleus gene expression atlas and epigenomic datasets from larvae reared with and without parental care. We find that the loss of parental care induces molecular stress, disrupting the expression of the protein chaperone Hsp83, which is a well-known molecular capacitor, alongside other putative mRNA chaperones. Moreover, our results suggest that parental care buffers development by maintaining an open, responsive chromatin landscape and redundant gene regulatory interactions. Overall, our work reveals that parental care shapes the storage, expression and release of genetic variation with broad implications for adaptation and evolution.

animal behavior and cognition↗

bioRxiv2026

Distinct mechanistic pathways of early tauopathy revealed by MAPT mutations

Tau pathology underlies a broad spectrum of neurodegenerative disorders, collectively termed tauopathies, yet these diseases exhibit striking heterogeneity in their biological mechanisms and clinical outcomes. The basis for this heterogeneity remains poorly understood. Here, we address this question using knock-in mouse models expressing two distinct frontotemporal dementia-associated tau mutations to define how different tau variants drive divergent pathogenic programs in vivo. We find that the two mutations give rise to fundamentally different trajectories of tau pathogenesis. One trajectory is marked by progressive tau hyperphosphorylation and cytoskeletal destabilization occurring in the absence of detectable tau seed formation. In contrast, an alternative trajectory is characterized by tau hypophosphorylation, early seed formation, and alterations in nucleotide metabolism and chromatin organization, without overt cytoskeletal disruption. With aging, tau in this latter pathway transitions to a hyperphosphorylated state and forms mature fibrillar aggregates. Genetic enhancement of {beta}-amyloid selectively accelerates fibril formation, particularly in the model exhibiting early seeding. Together, these findings demonstrate that distinct tau mutations can engage separable pathogenic mechanisms, providing a biological framework for the heterogeneity observed across tauopathies, and highlighting the need for mechanism-informed therapeutic strategies and patient stratification. O_FIG O_LINKSMALLFIG WIDTH=199 HEIGHT=200 SRC="FIGDIR/small/705716v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@11eb652org.highwire.dtl.DTLVardef@153cc53org.highwire.dtl.DTLVardef@8b670eorg.highwire.dtl.DTLVardef@1afaad_HPS_FORMAT_FIGEXP M_FIG C_FIG Graphical abstractSchematic representation comparing two trajectories of tau pathology. The S305N mutation promotes a 4R isoform shift, cytoskeletal damage and synapse loss, and accumulation of soluble hyperphosphorylated tau. Tau remains soluble even at old ages. In contrast, the P301S mutation generates hypophosphorylated, seed-competent tau that forms fibrils. The effect of amyloid is slow in the S305N, but results in accelerated acceleration of pathology in the P301S. Figure made with Biorender.com.

neuroscience↗

bioRxiv2025

Spatially Resolved Microglial Expression Around Aβ Plaques in Human Alzheimers Disease Tissue

Using microglia-enriched spatial transcriptomics on human Alzheimers disease tissue, we identify distinct gene expression changes across microglia located in direct contact with plaques, in periplaque regions, and in areas distant from plaques. We define a group of plaque contact-only microglial (PCOM) genes whose expression increases exclusively in microglia directly contacting plaques. These genes show significant overlap with previously reported gene sets, suggesting that many of the well-characterised disease-associated microglia (DAM) and other AD-related gene-expression signatures are only upregulated when microglia contact plaques. We further identify distinct co-expression networks associated with disease-relevant covariates, including an immune module linked to APOE genotype and a synaptic-mitochondrial module negatively associated with Braak stage. Finally, we compare the human dataset to our previously published data from 18-month-old AppNL-F mice, generated using the same experimental paradigm and demonstrate cross-species concordance in gene expression particularly within plaque-contacting microglia.

neuroscience↗

bioRxiv2025

Scalable human neuronal models of tauopathy producing endogenous seed-competent 4R tau

The accumulation of pathological four-repeat (4R) tau is central to several frontotemporal dementia (FTD) subtypes, but human neuronal models amenable to high-throughput screening of 4R tau-targeting therapies remain very limited. To address this, we developed iPSC-derived i3Neuron (i3N) lines expressing >75% 4R tau, driven by FTD splice-shifting mutations (S305N or S305N/IVS10+3). These neurons develop hyperphosphorylated tau and demonstrate somatodendritic mis-localization. Unlike other stem cell models of tauopathy, these i3N neurons develop endogenous seed-competent tau and present pFTAA-positive tau assemblies after 28 days in culture. For scalable screening, we CRISPR-engineered a HiBiT luminescence tag at the endogenous MAPT locus into the S305N/IVS10+3 iPSC line, enabling precise quantification of tau levels and pharmacological responses. The model responded predictably to compounds affecting tau clearance, demonstrating its suitability for drug discovery. Overall, this i3N platform recapitulates key features of 4R tauopathy and provides a robust system to identify therapeutic modulators of pathological tau.

neuroscience↗

bioRxiv2025

Transcriptomic analysis of repeat expansion-ataxias uncovers distinct non-neuronal cell type-specific signatures of disease across the human brain

Hereditary ataxias are a heterogeneous group of neurogenetic conditions characterised by the clinical syndrome of progressive loss of coordination from neurodegeneration of the cerebellum. A commonality across the most prevalent ataxias is the underlying disease mechanism secondary to expansions of short tandem DNA repeats. There is currently an incomplete understanding of the pathogenic mechanisms of these repeat expansion disorders, a core feature of which revolves around RNA-dysregulation. In this study, we used both bulk and single nuclear RNA-sequencing to study post-mortem brain tissue of human donors with a range of repeat-expansion ataxias to reveal further mechanistic insights. We compared post-mortem paired cerebellar and frontal cortex tissue bulk RNA-sequencing data from 23 ataxia patients and 22 sex-, age-matched controls from two brain banks (spinocerebellar ataxia (SCA)1, SCA2, SCA6, SCA7, SCA17, Friedreichs ataxia (FRDA), and 7 cases with unknown molecular diagnoses). We analysed bulk RNA-sequencing data for transcript usage, differential and cell-type-specific expression to transcriptomically profile these diseases. We also generated single nuclear RNA-sequencing data of the cerebellum from donors with SCA1, SCA2, SCA6 and FRDA to decipher changes in cell type proportions in the disease state. Using this approach, we found that: (i) despite the commonalities in the genetics of ataxia, there were components of their transcriptional signatures which were distinct; (ii) there were extensive transcriptional changes evident not only in the cerebellum but also the frontal cortex in ataxia cases; (iii) activation of immune and inflammatory pathways, as well as involvement of non-neuronal cell types was a feature of all ataxias to a lesser or greater extent. This study provides a novel resource to understand the mechanisms of disease in ataxia. Furthermore, taken together, these results highlight immune pathways and the role of non-neuronal cell types as early and potentially important therapeutic targets. These findings provide a map of transcriptomic changes in ataxia to further understanding of the underlying pathogenesis.

neuroscience↗

bioRxiv2023

The hagfish genome and the evolution of vertebrates

As the only surviving lineages of jawless fishes, hagfishes and lampreys provide a critical window into early vertebrate evolution. Here, we investigate the complex history, timing, and functional role of genome-wide duplications in vertebrates in the light of a chromosome-scale genome of the brown hagfish Eptatretus atami. Using robust chromosome-scale (paralogon-based) phylogenetic methods, we confirm the monophyly of cyclostomes, document an auto-tetraploidization (1RV) that predated the origin of crown group vertebrates [~]517 Mya, and establish the timing of subsequent independent duplications in the gnathostome and cyclostome lineages. Some 1RV gene duplications can be linked to key vertebrate innovations, suggesting that this early genomewide event contributed to the emergence of pan-vertebrate features such as neural crest. The hagfish karyotype is derived by numerous fusions relative to the ancestral cyclostome arrangement preserved by lampreys. These genomic changes were accompanied by the loss of genes essential for organ systems (eyes, osteoclast) that are absent in hagfish, accounting in part for the simplification of the hagfish body plan; other gene family expansions account for hagfishes capacity to produce slime. Finally, we characterise programmed DNA elimination in somatic cells of hagfish, identifying protein-coding and repetitive elements that are deleted during development. As in lampreys, the elimination of these genes provides a mechanism for resolving genetic conflict between soma and germline by repressing germline/pluripotency functions. Reconstruction of the early genomic history of vertebrates provides a framework for further exploration of vertebrate novelties.

genomics↗

bioRxiv2022

A single-cell atlas of bobtail squid visual and nervous system highlights molecular principles of convergent evolution

Although the camera-type eyes of cephalopods and vertebrates are a canonical example of convergent morphological evolution, the cellular and molecular mechanisms underlying this convergence remain obscure. We used genomics and single cell transcriptomics to study these mechanisms in the visual system of the bobtail squid Euprymna berryi, an emerging cephalopod model. Analysis of 98,537 cellular transcriptomes from the squid visual and nervous system identified dozens of cell types that cannot be placed in simple correspondence with those of vertebrate or fly visual systems, as proposed by Ramon y Cajal and J.Z. Young. Instead, we find an unexpected diversity of neural types, dominated by dopamine, and previously uncharacterized glial cells. Surprisingly, we observe changes in cell populations and neurotransmitter usage during maturation and growth of the visual systems from hatchling to adult. Together these genomic and cellular findings shed new light on the parallel evolution of visual system complexity in cephalopods and vertebrates.

evolutionary biology↗

bioRxiv2018

Reconstruction of the global neural crest gene regulatory network in vivo

Precise control of developmental processes is encoded in the genome in the form of gene regulatory networks (GRNs). Such multi-factorial systems are difficult to decode in vertebrates owing to their complex gene hierarchies and transient dynamic molecular interactions. Here we present a genome-wide in vivo reconstruction of the GRN underlying development of neural crest (NC), an emblematic embryonic multipotent cell population. By coupling NC-specific epigenomic and single-cell transcriptome profiling with genome/epigenome engineering in vivo, we identify multiple regulatory layers governing NC ontogeny, including NC-specific enhancers and super-enhancers, novel trans-factors and cis-signatures. Assembling the NC regulome has allowed the comprehensive reverse engineering of the NC-GRN at unprecedented resolution. Furthermore, identification and dissection of divergent upstream combinatorial regulatory codes has afforded new insights into opposing gene circuits that define canonical and neural NC fates. Our integrated approach, allowing dissection of cell-type-specific regulatory circuits in vivo, has broad implications for GRN discovery and investigation.

developmental biology↗

bioRxiv2018

A genome-wide assessment of the ancestral neural crest gene regulatory network

The neural crest is an embryonic cell population that contributes to key vertebrate-specific features including the craniofacial skeleton and peripheral nervous system. Here we examine the transcriptional profiles and chromatin accessibility of neural crest cells in the basal sea lamprey, in order to gain insight into the ancestral state of the neural crest gene regulatory network (GRN) at the dawn of vertebrates. Transcriptome analyses reveal clusters of co-regulated genes during neural crest specification and migration that show high conservation across vertebrates for dynamic programmes like Wnt modulation during the epithelial to mesenchymal transition, but also reveal novel transcription factors and cell-adhesion molecules not previously implicated in neural crest migration. ATAC-seq analysis refines the location of known cis-regulatory elements at the Hox-2 locus and uncovers novel cis-regulatory elements for Tfap2B and SoxE1. Moreover, cross-species deployment of lamprey elements in zebrafish reveals that the lamprey SoxE1 enhancer activity is deeply conserved, mediating homologous expression in jawed vertebrates. Together, our data provide new insight into the core elements of the GRN that are conserved to the base of the vertebrates, as well as expose elements that are unique to lampreys.

developmental biology↗

bioRxiv2017

From pioneer to repressor: Bimodal foxd3 activity dynamically remodels neural crest regulatory landscape in vivo

The neural crest (NC) is a transient embryonic stem cell population characterised by its multipotency and broad developmental potential. Here, we perform NC-specific transcriptional and epigenomic profiling of foxd3-mutant versus wild type cells in vivo to define the gene regulatory circuits controlling NC specification. Together with global binding analysis obtained by foxd3 biotin-ChIP and single cell profiles of foxd3-expressing premigratory NC, our analysis shows that during early steps of NC formation, foxd3 acts globally as a pioneer factor to prime the onset of genes regulating NC specification and migration by re-arranging the chromatin landscape, opening cis-regulatory elements and reshuffing nucleosomes. Strikingly, foxd3 then switches from an activator to its canonical role as a transcriptional repressor. Taken together, these results demonstrate that foxd3 acts bimodally in the neural crest as a switch from permissive to repressive nucleosome/chromatin organisation to maintain stemness and define cell fates.

developmental biology↗

bioRxiv2017

Generation Of A Double Binary Transgenic Zebrafish Model To Study Myeloid Gene Regulation In Response To Melanocyte Transformation

A complex network of inflammation succeeds somatic cell transformation and malignant disease. Immune cells and their associated molecules are responsible for detecting and eliminating cancer cells as they establish themselves as the precursors of a tumour. By the time a patient has a detectable solid tumour, cancer cells have escaped the initial immune response mechanisms. To date, no model exists for studying the underlying mechanisms that govern the initial phase of the immune response when transformed cells become precursors of cancer. Here we describe the development of a double binary zebrafish model designed for exploring regulatory programming of the myeloid cells as they respond to oncogenic transformed melanocytes. A hormone-inducible binary system allows for temporal control of different Ras-oncogenes (NRasK61Q, HRasG12V, KRasG12V) expression in melanocytes, enabling analysis of melanocyte transformation and melanoma initiation. This model was coupled to binary cell-specific biotagging models allowing in vivo biotinylation and subsequent isolation of macrophage or neutrophil nuclei for regulatory profiling of their active transcriptomes. Nuclear transcriptional profiling of neutrophils, performed for the first time as they respond to the earliest precursors of melanoma in vivo, revealed an intricate landscape of regulatory factors that may promote progression to melanoma including fgf1, fgf6, cathepsin H, cathepsin L, galectin 1 and galectin 3. The model presented here provides a powerful platform to study the myeloid response to the earliest precursors of melanoma.\n\nSummary StatementWe present an innovative double binary zebrafish model for exploring the underlying regulatory mechanisms that govern the myeloid response mechanisms at the onset of melanoma.

molecular biology↗