Biology subjects

Fedorov, A.

Publications and source records attributed to Fedorov, A..

6 recordsLinked to original sources

bioRxiv2026

XRN1-dependent RNA homeostasis regulates hepatitis D virus

Hepatitis delta virus (HDV) infection causes the most severe form of viral hepatitis, yet the host mechanisms restricting HDV replication remain poorly understood. Although HDV infection activates the MDA5-LGP2 pathway and induces robust interferon (IFN) responses, these antiviral programs have limited impact on viral replication. Here we identify the 5-3 exoribonuclease XRN1 as a key regulator of HDV infection. Loss of XRN1 in hepatoma cells increased double-stranded RNA (dsRNA) levels and induced interferon-stimulated genes (ISGs), including MDA5 and MAVS, and limited HDV infection. XRN1 deficiency enhanced ADAR1-mediated RNA editing, revealing a dynamic interplay between endogenous dsRNA metabolism and antiviral sensing. Inhibition of type I IFN signaling restored MDA5 expression and rescued HDV replication in XRN1-deficient cells. To identify the downstream effectors responsible for this restriction, we combined transcriptomic profiling with functional siRNA screening and identified DUSP5 and SIRPA as previously unrecognized ISGs with anti-HDV activity. Together, our findings establish XRN1 as a gatekeeper of dsRNA homeostasis that controls HDV replication through innate immune activation and reveals host antiviral effectors that may provide therapeutic opportunities for chronic hepatitis D.

molecular biology↗

bioRxiv2026

Nascent transcripts of LL2R tandem repeat nucleate locus-specific RNP condensates recruiting splicing factors

Spatial organization of the cell nucleus is increasingly understood to be governed by non-coding architectural RNAs that seed the formation of biomolecular condensates. However, the genomic origins and mechanistic principles by which specific architectural RNAs orchestrate ribonucleoprotein (RNP) compartments remain poorly defined. Here, we characterised a novel non-coding architectural RNA that nucleates the formation of a locus-associated membraneless nuclear compartment. Using a combination of T2T genomic, transcriptomic, and high-resolution mapping on giant lampbrush chromosomes, we identified an array of non-coding LL2R tandem repeats on the long arm of chicken chromosome 2. The LL2R tandem repeat array is slowly transcribed by a convoy of RNA polymerases II as a single transcription unit from a retrotransposon promoter. With the use of scanning electron and super-resolution microscopy for detailed analysis, we demonstrate that nascent LL2R repeat transcripts are retained at the site of their transcription and recruit multiple sets of core splicing factors, including TMG-capped snRNAs, core snRNP proteins, and serine/arginine-rich proteins SRRM2 and SC35 that contain intrinsically disordered regions, thus seeding nuclear domain formation. At the same time, the RNP-matrix of the LL2R repeat transcription unit lacks hnRNP L, hnRNP K, and SFPQ, widely distributed along normal transcription loops that bear nascent gene transcripts. In contrast to pre-mRNAs, strand-specific LL2R tandem repeat-containing RNA contains more than threefold excess of predicted donor splice sites compared to acceptor splice sites and is depleted in polyadenylation signals. We suggest that stalling of elongating RNA polymerases at LL2R transcription units and delay in 3 end cleavage may be caused by a deficiency of co-transcriptional splicing of nascent LL2R repeat transcripts. LL2R repeat-containing RNA also forms non-diffusible RNP-aggregates enriched by splicing factors that could serve as a site of post-transcriptional splicing. Our findings reveal how tandem repeat-derived RNAs drive the assembly of oocyte nuclear condensates, providing a functional template for understanding the formation of closely related nuclear speckles and nuclear stress bodies across eukaryotes.

cell biology↗

bioRxiv2025

Multimodal Fusion Analysis of Florbetapir PET and Multiscale Functional Network Connectivity in Alzheimer's Disease

Accumulation of amyloid-beta plaques and disruption of intrinsic brain networks are two important characteristics of Alzheimers disease (AD), yet the relationship between amyloid accumulation and network dysfunction remains unclear. In this study, we integrated [18F]Florbetapir PET and resting-state fMRI (rsfMRI) derived Functional Network Connectivity (FNC) from 552 temporally matched longitudinal PET-rsfMRI sessions across 395 participants spanning Cognitively Normal (CN), Mild Cognitive Impairment (MCI), and AD stages. With a model order of 11, joint Independent Component Analysis (jICA) was applied to the fused PET-FNC data, identifying 11 stable components, of which 9 PET-derived components corresponded to previously characterized brain regions or networks. The multimodal analysis revealed disease progression markers, including (1) a pattern of reduced subject loadings across clinical stages (CN > MCI > AD) in white matter and cerebellar regions, reflecting structural degeneration; (2) increased amyloid accumulation in affected individuals in grey matter regions, particularly in frontal, sensorimotor, extended hippocampal, and default mode network (DMN) regions, accompanied by functional connectivity alterations that reflected both compensatory and disruptive network dynamics. We identified PET-derived components that captured distinct stages of disease progression, with the DMN component emerging as a late-stage biomarker and a white matter component showing early-stage changes with limited progression thereafter. Additionally, several components showed significant variation in loadings between APOE{varepsilon} 4 carriers and non-carriers, linking the multimodal signatures to a well-established genetic risk factor for AD.

neuroscience↗

bioRxiv2024

The first chicken oocyte nucleus whole transcriptomic profile defines the spectrum of maternal mRNA and non-coding RNA genes transcribed by the lampbrush chromosomes

Lampbrush chromosomes, with their unusually high rate of nascent RNA synthesis, provide a valuable model for studying the mechanisms of global transcriptome up-regulation. Here, we aimed to establish a full set of sequences transcribed on the lateral loops of chicken lampbrush chromosomes. For the first time, a whole-genomic profile of transcription along the entire length of all lampbrush chromosomes in the chicken karyotype including sex chromosomes and dot chromosomes was obtained. For that, we performed RNA-seq of oocyte nuclear and cytoplasmic total RNA, poly(A) RNA and small RNA libraries and aligned expressed RNA sequences against the chicken genome. This led to the identification of a full spectrum of maternal RNAs that accumulate in the nucleus and cytoplasm of chicken oocytes at the lampbrush chromosome stage, are then transferred to the zygote and can be used during the early stages of embryogenesis, including transcripts of protein-coding genes, long non-coding RNAs and small housekeeping non-coding RNAs. We also present the first high-throughput transcriptome characterisation of miRNAs and piRNAs in chicken oocytes at the lampbrush chromosome stage. Major targets of predicted piRNAs include CR1 and LTR containing retrotransposable elements. Transcription of tandem repeat arrays including 41bp higher-order repeats as well as unique centromere sequences was demonstrated by alignment against the whole telomere-to-telomere chromosome assemblies. We show that transcription of telomere-derived RNAs, including telomeric repeat-containing RNA (TERRA) and subtelomeric repeat-containing RNA, is initiated at adjacent LTR elements. With nuclear RNA-seq, we obtained information about a wider set of transcripts, including long non-coding RNAs retained in the nucleus and stable intronic sequence RNAs (sisRNAs). We identified 5 UTR sisRNAs that may potentially support host gene transcription both during oogenesis and after activation of the embryonic genome. For a number of protein-coding genes, we visualised nascent transcripts and demonstrated their co-transcriptional splicing on the lateral loops of lampbrush chromosomes by RNA-FISH. The nuclear RNA-seq profile predicted the chromomere-loop organisation of the genomic regions. During oocyte maturation, transcriptional unit boundaries were maintained, while transcriptional output tended to decrease. We conclude that cytoplasmic and nuclear transcripts emerge from nascent transcripts on the lateral loops of lampbrush chromosomes. Most of gene transcripts are initiated at promoters, normally spliced, terminated and polyadenylated. The set of genes transcribed on the lampbrush chromosomes is required for basic cellular processes, is characterised by a broad expression pattern and is similar to sets of genes expressed in other hypertranscriptional systems. We conclude that hypertranscription on the lateral loops of giant lampbrush chromosomes is the main mechanism for synthesising large amounts of transferred to the embryo maternal RNA for thousands of genes.

cell biology↗

bioRxiv2023

Z-Flipon Variants reveal the many roles of Z-DNA and Z-RNA in health and disease

Identifying roles for Z-flipons remains challenging given their dynamic nature. Here we perform genome-wide interrogation with the DNABERT transformer algorithm trained on experimentally identified Z-DNA sequences. We show Z-flipons are enriched in promoters and telomeres and overlap quantitative trait loci for RNA expression, RNA editing, splicing and disease associated variants. Surprisingly, many effects are mediated through Z-RNA formation. We describe Z-RNA motifs present in SCARF2, SMAD1 and CACNA1 transcripts and others in non-coding RNAs. We also provide evidence for another Z-RNA motif that likely enables an adaptive anti-viral intracellular defense through alternative splicing of KRAB domain zinc finger proteins. An analysis of OMIM and gnomAD predicted loss-of-function datasets reveals an overlap of predicted and experimentally validated Z-flipons with disease causing variants in 8.6% and 2.9% of mendelian disease genes respectively, with frameshift variants present in 22% of cases. The work greatly extends the number of phenotypes mapped to Z-flipon variants.

genomics↗

bioRxiv2018

Deep Residual Learning for Neuroimaging: An application to Predict Progression to Alzheimer’s Disease

This work investigates the suitability of deep residual neural networks (ResNets) for studying neuroimaging data in the specific application of predicting progression from mild cognitive impairment (MCI) to Alzheimers disease (AD). We focus on predicting the subset of MCI individuals that would progress to AD within three years (progressive MCI) and the subset of MCI individuals that do not progress to AD within this period (stable MCI). This prediction was conducted first as a standard binary classification task by training a ResNet architecture using MCI individuals only, followed by a modified domain transfer learning version that additionally trained on the AD and cognitively normal (CN) individuals. For this modified inter-MCI classification task, the ResNet architecture achieved better than state-of-the-art performance in predicting progression to AD using structural MRI data alone (> 7% than the second best performing method), within 1% of the state-of-the-art performance considering learning using multiple structural modalities as well, and a significant performance improvement over the classical support vector machine learning framework (p = 2.5762 x 10-8). The learnt surrogate (i.e. cross-validation-fold-specific) models and the final predictive model (trained on all data) in this modified classification task showed highly similar peak activations, significant correspondence of which in the medial temporal lobe and other areas could be established with previous reports in AD literature, thus further validating our findings. Our results highlight the possibility of early identification of modifiable risk factors for understanding progression to AD using similar advanced deep learning architectures.

neuroscience↗