Biology subjects

Bokarewa, M. I.

Publications and source records attributed to Bokarewa, M. I..

6 recordsLinked to original sources

bioRxiv2026

Neurostructural and molecular evidence of advanced brain aging in rheumatoid arthritis

Chronic systemic inflammation has been implicated in age-related neurodegeneration, but whether rheumatoid arthritis (RA) is associated with accelerated brain aging remains unclear. We combined structural magnetic resonance imaging (MRI), circulating neurodegeneration biomarkers, and peripheral monocyte transcriptomics to investigate brain aging in RA across two independent cohorts. A brain-age prediction model trained in healthy controls from the IXI imaging dataset was applied to RA patient cohorts from Gothenburg (n = 71) and Glasgow (n = 50). RA was associated with significantly elevated corrected brain-age gap relative to healthy controls (+6.5 years, 95% CI 4.2-8.8 years, p = 1.2 x 10-7), with substantially stronger effects in patients [≥]60 years. Older RA patients demonstrated a significant ventricular enlargement together with reduced frontal and parietal lobe volumes. Serum brain-derived tau and glial fibrillary acidic protein levels were elevated in RA. The increased brain-age gap was associated with altered myeloid transcriptional signatures. These findings demonstrate that RA is associated with age-related neurostructural alterations consistent with accelerated brain aging.

neuroscience↗

bioRxiv2025

CD5L insufficiency exacerbates skeletal joint damage in rheumatoid arthritis

CD5L is an immunoregulatory protein induced during inflammation and makes a life-saving contribution in infection and sepsis. Here, we explored the overall impact of CD5L in rheumatoid arthritis (RA). Using experimental RA models, we demonstrated an early surge of CD5L expression in wild-type mice, as well as a higher incidence and increased severity of arthritis in CD5L-deficient mice. In the blood, CD5L-deficient mice exhibited enhanced inflammation, a higher proportion of CD11b mononuclear cells, and elevated levels of IL-1{beta}, IL-17, and IFN-{psi}, particularly at the pre-clinical stage of arthritis. In human RA, mononuclear cells conditioned with CD5L, as well as endogenous CD5L production, were associated with reduced CD11b expression, increased IL-10 and PD-L1 production, and an enrichment of non-classical CD16+ monocytes. Analysis of the CD5L-dependent transcriptome in CD14 cells from RA patients revealed the acquisition of an efferocytosis profile, with upregulation of C1Q subunits, GAS6, AXL, and ALOX15B. It also showed signs of insufficient cargo processing, which dampens the resolution of inflammation, permits the expansion of IFN-primed non-classical monocytes, and correlates strongly with joint damage accrual. Despite markedly low CD5L levels in the synovium, RA synovial tissue was enriched with non-classical monocytes carrying the GAS6-AXL signature, which fosters osteoclast progenitors. In conclusion, this study demonstrates that the anti-inflammatory and inflammation-resolving properties of CD5L in experimental and human RA are mediated through the induction of efferocytosis-related and IFN-primed monocyte programs. This harbors a potential risk of uncontrolled invasion of non-classical monocytes into the synovial tissue, leading to joint structural damage. The complex role of CD5L in inflammation and disease outcomes requires careful consideration of the disease phase and experimental context.

immunology↗

bioRxiv2025

Functional Group Composition: The Blueprint for Protein Interactions

Understanding the complex landscape of protein interactions, especially those involving intrinsically disordered proteins (IDPs), is fundamental yet challenging due to their structural heterogeneity and flexibility. Traditional sequence-based homology methods frequently fall short in characterizing IDP functions and interactions. Here, we present a novel approach leveraging supervised and unsupervised machine learning techniques, focusing exclusively on the compositional features of proteins. An Edmond-Ogston-inspired mixing model can reliably predict the degree of survivin (BIRC5) binding as a function of peptide composition alone, revealing a first interesting connection with the composition diagrams of chemical thermodynamics. By representing protein sequences through their functional group compositions, we demonstrate that specific compositions robustly predict binding interactions with survivin, an important human protein in cellular regulation pathways. Experimental validation via peptide microarray confirms the predictive power of our simplified compositional model, independent of exact amino acid sequences. Extending this method across the human proteome, we identified distinct compositional signatures correlating with survivin interactions and revealed fine grained biologically meaningful functional clusters based on compositional similarity. Our findings suggest a compositional blueprint underpinning protein interactions, offering a powerful, simplified framework to decode complex biological networks.

systems biology↗

bioRxiv2025

Insulin exerts epigenetic control of joint-specific memory T cells in rheumatoid arthritis

BackgroundInsulin has epigenetic effect influencing gene expression. High peripheral insulin concentrations promote insulin resistance in autoimmunity. Oncoprotein survivin/BIRC5 modulates glucose metabolism through chromatin binding and propagates IFNg effects in CD4+ cells. In this study, we explored how insulin influences chromatin binding and metabolic activity in autoimmune CD4+ cells of patients with rheumatoid arthritis (RA). MethodsWe profiled the metabolic activity of CD4+ cell clusters using single-cell transcriptome analysis in blood, synovial fluid and synovial tissue of RA patients. Through chromatin immunoprecipitation and sequencing, we identified the genes controlled by deposition of survivin and acetylated lysine 27 on histone H3 (H3K27ac) in CD4+ cells. Treating CD4+ cells with insulin and histone deacetylase inhibitors (HDACi), we identified changes in H3K27ac, linked those to transcription of the H3K27-survivin-controlled genes and the pathogenic phenotype of CD4+ cells using flow cytometry. Finally, we explored if anti-diabetic and anti-rheumatic drugs affect the metabolic profile and memory phenotype of the metabolic active CD4+ cells. ResultsTranscription of survivin/BIRC5 and histone acetylation enzymes strongly correlate with active metabolism in blood CD4+ cells of RA patients. In RA synovial tissue, these BIRC5hi active T cell clusters are inflammatory, exhausted, and memory-like. Genome co-deposition of H3K27ac-survivin pinpointed the insulin-dependent genes in metabolic active CD4+ cells. These genes favored histone acetylation by suppressing methylating enzymes EZH2 and KMT2A, and T cell development by activating CD27, CD3G, and SCIMP. Inhibition of histone deacetylation reverted these transcriptional effects and supported cellular sensitivity to insulin. Insulin stimulation increased H3K27ac and together with HDACi, suppressed PDCD1 and IFNg transcription and production in CD4+CD27+CD45RO+ memory T cells. Immune modulation impacted metabolic activity and synergized with the effect of histone acetylation on insulin responsiveness in RA patients. ConclusionsRA synovia is enriched with the metabolic active BIRC5hiCD4+ T cell clusters. The metabolic activity of these cells is histone acetylation-dependent and mediates insulin effects through the H3K27ac-survivin epigenetic mechanism. Increasing plasma insulin levels when combined with insulin sensitivity, can be protective in RA dearmoring effector T cell function. Hence, increasing the insulin sensitivity by enabling histone acetylation presents a reasonable interventional goal to restore immune cell homeostasis in RA.

immunology↗

bioRxiv2024

Survivin in synergy with BAF/SWI complex binds bivalent chromatin regions and activates DNA damage response in CD4+ T cells

This study explores a regulatory role of oncoprotein survivin on the bivalent regions of chromatin (BvCR) characterized by concomitant deposition of trimethylated lysine of histone H3 at position 4 (H3K4me3) and 27 (H3K27me3). Intersect between BvCR and chromatin sequences bound to survivin demonstrated their co-localization on cis-regulatory elements of genes which execute DNA damage control in primary human CD4+ cells. Survivin anchored BRG1-complex to BvCR to repress DNA damage repair genes in IFN{gamma}-stimulated CD4+ cells. In contrast, survivin inhibition shifted the functional balance of BvCR in favor of H3K4me3, which activated DNA damage recognition and repair. Co-expression of BRG1, survivin and IFN{gamma} in CD4+ cells of patients with rheumatoid arthritis identified arthritogenic BRG1hi cells abundant in autoimmune synovia. Immunomodulating drugs inhibited the subunits anchoring BRG1-complex to BvCR, which changed the arthritogenic profile. Together, this study demonstrates the function of BvCR in DNA damage control of CD4+ cells offering an epigenetic platform for survivin and BRG1-complex targeting interventions to combat autoimmunity. SummaryThis study shows that bivalent chromatin regions accommodate survivin which represses DNA repair enzymes in IFN{gamma}-stimulated CD4+ T cells. Survivin anchors BAF/SWI complex to these regions and supports autoimmune profile of T cells, providing novel targets for therapeutic intervention.

immunology↗

bioRxiv2021

Chromatin binding of survivin regulates glucose metabolism in the IFN-g producing CD4+T cells

Interferon-gamma (IFN{gamma}) producing T cells develop metabolic adaptation required for their effector functions in tumour biology, autoimmunity and antiviral defence. Using sorted CD4+ cells we demonstrated that glycolytic switch and high glucose uptake in IFN{gamma}-producing cells was associated with survivin expression. Inhibition of survivin restored glycolysis by upregulating the transcription of phosphofructokinase PFKFB3 and reducing glucose uptake. Integration of the whole-genome sequencing of the chromatin immunoprecipitated with survivin with transcription changes in CD4+ cells after survivin inhibition revealed co-localization of survivin, IRF1 and SMAD3 in the regulatory elements paired to the differentially expressed genes. Western blot demonstrated direct binding of survivin to IRF1 and SMAD3. Functionally, inhibition of survivin repressed IFN{gamma} signalling and activated SMAD3-dependent protein remodelling, which resulted in the effector-to-memory transition of CD4+ cells. These findings demonstrate the key role of survivin in IFN{gamma}-dependent metabolic adaptation and identify survivin inhibition as an attractive strategy to counteract these effects.

immunology↗