Biology subjects

Tvorogova, A. V.

Publications and source records attributed to Tvorogova, A. V..

8 recordsLinked to original sources

bioRxiv2026

Accelerated Aging Signatures in 3D Genome Organization and Transcriptome in Schizophrenia

Schizophrenia is a severe neuropsychiatric disorder that affects the behavioral, emotional and cognitive state of patients. Despite its substantial heritability, the molecular etiology of the disease remains poorly understood. Many schizophrenia-associated genetic variants reside in non-coding regions, and exert their effects through distal regulatory elements of the genome. In this context, the three-dimensional organization of the genome is expected to play a decisive role in establishing contacts between these regulatory elements and their target genes, thereby mediating schizophrenia-associated dysregulation of gene expression. Here, we present a novel Hi-C dataset providing an unprecedented view of three-dimensional genome organization in post-mortem schizophrenia brain samples. Our findings indicate that most changes occur at long-range genomic distances while local architecture of topologically-associated domains remains largely intact. However, neurons display localized and functionally relevant loop differences, particularly in regulatory regions associated with neurodevelopmental processes. Global characteristics of higher-order chromatin organization show accelerated aging alteration pattern in schizophrenia, and downstream analysis of transcriptomic data in schizophrenia brain samples further confirms that schizophrenia is associated with accelerated aging.

bioinformatics↗

bioRxiv2025

Ultra-long-range Polycomb-coupled interactions underlie subtype identity of human cortical neurons

Regulation of gene expression by Polycomb group (PcG) proteins orchestrates neural development and cell-type specification. However, the mechanisms by which neural progenitor cells diversify into the myriad cell types of the human brain remain poorly understood. Here, we investigate the role of Polycomb pro-teins in shaping the single-cell 3D genome, transcriptome, and chromatin binding landscape of the developing and adult human cortex. We show that PcG proteins establish a network of long-range repressive interactions encompassing loci with neuronal marker genes. These interactions occur in a neuron-type-dependent manner, selectively targeting genes that must remain silenced in a given cell type. These interactions are present in fetal neurons and increase markedly in strength after birth. Our results highlight PcG proteins as key regulators of neuronal cell fate specification in the human brain.

genomics↗

bioRxiv2025

Fetal signatures in the 3D genome of iPSC-derived neurons: implications for disease modeling

Induced pluripotent stem cells (iPSCs) have revolutionized neuroscience, providing an approach to generate patient-specific neurons for modeling of neurological diseases. However, it remains unclear how closely iPSC-derived neurons replicate the chromatin architecture of authentic brain neurons. Here, we uniformly process datasets for 228 human and 89 mouse Hi-C and Snm3C-seq samples of different cell subtypes merged into 96 high-coverage contact maps used to examine chromatin features ranging from chromatin compartments and topologically associating domains (TADs) to chromatin loops, Polycomb-mediated contacts, and frequently interacting regions (FIREs). We find that iPSC-derived neurons largely retain chromatin state of undifferentiated cells and resemble fetal rather than mature neurons. iPSC-derived neurons exhibit unusually strong compartmentalization, an enrichment of developmental genes at TAD borders, and a marked reduction of long-range repressive Polycomb-mediated contacts that typically silence early fetal programs. Although immature, iPSC-derived neurons offer advantages for modeling interactions between disease-associated SNPs and target genes, as many psychiatric disorders have neurodevelopmental origins. Integrating iPSC-derived and postmortem neuronal datasets therefore provides complementary insights into the chromatin landscape underlying disease-associated interactions. Our study offers a valuable Hi-C resource for the community and provides a detailed comparison of chromatin architecture throughout neuronal maturation, underscoring its importance for validating neuronal models and providing a robust framework for future studies.

genomics↗

bioRxiv2025

Eg5 Inhibitor SB743921 Causes p53-Dependent Cell Cycle Arrest, Senescence and Death in Tumor Cells

Mitotic inhibitors, such as Vinca alkaloids and taxanes, are one of the most effective chemotherapeutic agents used in the clinic. Despite their advantages, there are drawbacks to their use - primarily development of resistance and a high rate of side-effects, including damage to non-proliferating tissues. A range of new inhibitors targeting mitosis, whose activity does not depend on the binding to tubulin, are currently tested in clinical trials. Among such agents, inhibitors of Eg5 kinesin are highly promising due to their high activity and specificity. Here we show that compared to other drugs that target mitosis, an Eg5 inhibitor, SB743921, preferentially eliminates TP53-mutated cells and induces irreversible senescence, even after the drug washout, regardless of the p53 status. These effects are not defined by the immediate block of mitosis where SB743921 and a clinically used mitotic inhibitor Ixabepilone induce similar rates of mitotic arrest, apoptosis and induction of p53 and p21, but rather a long-term reaction, with absence of proteins required for replication, such as Cyclin A, E2F1, pRB. While after the washout Ixabepilone-treated cells can exit senescence and resume proliferation, cells treated with SB743921 did not exit the senescent state and did not resume proliferation as based on SA-{beta}-galactosidase staining and EdU incorporation. The remaining senescent cells were effectively eliminated by Bcl2/Bcl-xL/Bcl- w inhibitor ABT-263, showing a potential of the combinational therapy with senolytic drugs. In total, we show the capacity of Eg5-targeting drugs for therapy of high-risk TP53-mutated tumors, which are potentially resistant to clinically approved mitotic inhibitors.

cancer biology↗

bioRxiv2023

Knockout of cyclin dependent kinases 8 and 19 leads to depletion of cyclin C and suppresses spermatogenesis and male fertility in mice

Paralogs CDK8 and CDK19 are regulatory kinases associated with the transcriptional Mediator complex. We have e generated mice with the systemic inducible Cdk8 knockout on the background of Cdk19 constitutive knockout. Cdk8/19 double knockout (iDKO) males, but not single Cdk8 and Cdk19 KO, had an atrophic reproductive system and were infertile. The iDKO males lacked postmeiotic spermatids and spermatocytes after meiosis I pachytene. Testosterone levels were decreased whereas the amounts of the luteinizing hormone were unchanged. Single cell RNA sequencing showed marked differences in the expression of steroidogenic genes (such as Cyp17a1, Star and Fads) in Leydig cells concomitant with alterations in Sertoli cells and spermatocytes likely associated with impaired synthesis of steroids. Star and Fads were also downregulated in cultivated Leydig cells after iDKO. The treatment of primary Leydig cells culture with a CDK8/19 inhibitor did not induce the same changes in gene expression as iDKO, and prolonged treatment of mice with a CDK8/19 inhibitor did not affect the size of testes. iDKO, in contrast to single knockouts or treatment with a CDK8/19 kinase inhibitor, led to depletion of cyclin C (CcnC), the binding partner of CDK8/19 that has been implicated in CDK8/19-independent functions. This suggests that the observed phenotype was likely mediated through kinase-independent activities of CDK8/19, such as CcnC stabilization.

developmental biology↗

bioRxiv2023

Extensive long-range polycomb interactions and weak compartmentalization are hallmarks of human neuronal 3D genome

Chromatin architecture regulates gene expression and shapes cellular identity, particularly in neuronal cells. Specifically, polycomb group (PcG) proteins enable establishment and maintenance of neuronal cell type by reorganizing chromatin into repressive domains that limit the expression of fate-determining genes and sustain distinct gene expression patterns in neurons. Here, we map the 3D genome architecture in neuronal and non-neuronal cells isolated from the Wernickes area of four human brains and comprehensively analyze neuron-specific aspects of chromatin organization. We find that genome segregation into active and inactive compartments is greatly reduced in neurons compared to other brain cells. Furthermore, neuronal Hi-C maps reveal strong long-range interactions, forming a specific network of PcG-mediated contacts in neurons that is nearly absent in other brain cells. These interacting loci contain developmental transcription factors with repressed expression in neurons and other mature brain cells. But only in neurons, they are rich in bivalent promoters occupied by H3K4me3 histone modification together with H3K27me3, which points to a possible functional role of PcG contacts in neurons. Importantly, other layers of chromatin organization also exhibit a distinct structure in neurons, characterized by an increase in short-range interactions and a decrease in long-range ones.

genomics↗

bioRxiv2023

Lung lipid deposition in pneumonias of viral and non-viral aetiology

Pneumonia is an acute respiratory disease of varying etiology that has drawn much attention during the COVID-19 pandemic. Among the many thoroughly studied aspects of pneumonia, lipid metabolism has not been sufficiently addressed. Here, we investigated lipid deposition in the post mortem lung specimens of patients who died from COVID-19 and non-COVID-19 pneumonias. We used semi-thin sections and cryosections stained with Sudan III to visualize lipid droplet deposition within cells and in the extracellular space, most notably in small lung vessels. Electron microscopy analysis of the ultrathin sections was used to confirm the homogeneous structure of the droplets. Morphometric analysis revealed that the area of lipid deposition was increased in pneumonia compared to control lung tissue. Likewise, it was increased in the macroscopically inflamed vs. the macroscopically intact area of the same pneumonia lung. The lipid profiling by chromato-mass spectrometry revealed that lipid droplet accumulation in pneumonia was associated with a specific fatty acid content of the inflamed lung tissue. The gene expression analysis pointed to changes of lipid metabolism in the inflamed lung tissue compared to control lungs. Taken together, our data indicate a number of morphologic and metabolic changes associated with inflammation and common for pneumonias of different etiologies that likely contribute to pneumonia pathogenesis. Therefore, targeting lipid metabolism can be considered a new therapeutic strategy.

pathology↗

bioRxiv2021

Mechanisms and evolutionary implications of integration of different functions within HIV-1 Tat

During evolution, viruses had to adapt to an increasingly complex environment of eukaryotic cells. Viral proteins that need to enter the cell nucleus or associate with nucleoli possess nuclear localization signals (NLSs) and nucleolar localization signals (NoLSs) for nuclear and nucleolar accumulation, respectively. As viral proteins are relatively small, acquisition of novel sequences seems to be a more complicated task for viruses than for eukaryotes. Here, we carried out a comprehensive analysis of the basic domain (BD) of HIV-1 Tat to show how viral proteins might evolve with NLSs and NoLSs without an increase in protein size. The HIV-1 Tat BD is involved in several functions, the most important being the transactivation of viral transcription. The BD also functions as an NLS, although it is substantially longer than a typical NLS. It seems that different regions in the BD could function as NLSs due to its enrichment with positively charged amino acids. Additionally, the high positive net charge inevitably causes the BD to function as an NoLS through a charge-specific mechanism. The integration of NLSs and NoLSs into functional domains enriched with positively charged amino acids might be a mechanism that allows the condensation of different functional sequences in small protein regions and, as a result, to reduce protein size, influencing the origin and evolution of NLSs and NoLSs in viruses.

evolutionary biology↗