Biology subjects

Sokolova, V.

Publications and source records attributed to Sokolova, V..

6 recordsLinked to original sources

bioRxiv2026

MacroH2A-Mediated Gene Repression through Nucleosome Compaction and Remodeling Inhibition

MacroH2A (mH2A) is a histone variant primarily implicated in heterochromatin maintenance and transcriptional repression, yet how its conserved histone-fold and its variant-specific domains reshape chromatin to enforce gene silencing remains poorly understood. Here, we dissect the domain-specific contributions of mH2A to nucleosome dynamics and chromatin remodeling. We show that, in addition to its linker region, the C-terminal tail of mH2A histone-fold also stabilizes nucleosome entry/exit DNA. Cryo-EM analysis reveals that this C-terminus tracks along nucleosomal DNA toward the dyad, adopting an on-dyad binding mode reminiscent of linker histone H1. Additionally, the mH2A linker potently inhibits DNA translocation by both the INO80 and Chd1 chromatin remodelers, while the histone fold selectively suppresses INO80 activity. In contrast, the macro domain has no detectable impact on terminal DNA accessibility or remodeling. Together, our results uncover a previously unappreciated architectural role for the mH2A histone fold and establish the linker domain as a dominant regulator of nucleosome dynamics and chromatin remodeling, providing a mechanistic framework for how mH2A enforces transcriptional repression.

biochemistry↗

bioRxiv2025

Interrogation of retinal lipofuscin by fluorescence lifetime imaging microscopy

Age-related macular degeneration is a disease that affects the middle part of the vision and involves pathological alterations in the retinal pigment epithelium. Accurate and timely evaluation of the retinal pigment epithelium is a cornerstone of effective treatment planning. In this study, we present the development of a preclinical method for early diagnostics of age-related macular degeneration using time and spectral characteristics of fluorescence of lipofuscin granules from retinal pigment epithelium. Using the unique system based on asuperconducting single-photon detector and time-correlated single-photon counting electronics integrated in the confocal laser scanning microscope we determined the parameters of fluorescence (distribution long and short fluorescence lifetime components and their contribution to the total fluorescence signal as well as fluorescence spectral shift) that have a diagnostic value for differentiation of the normal and pathological states in the degenerative diseases of the retina and retinal pigment epithelium.

biophysics↗

bioRxiv2025

Glioblastoma stem cell morphotypes convey distinct cell states and clinically relevant functions

Glioblastoma (GBM) is an aggressive brain tumor and an unmet clinical need due to its invasiveness and therapy-resistance. These features are driven by glioblastoma stem cells (GSCs), which exhibit remarkable functional heterogeneity. However, GSC transcriptional profiling alone cannot predict clinically relevant behaviors. Here, we developed CellShape-seq, a spatial transcriptomics platform that integrates cell morphology with transcriptome. This identified three GSC morphoclasses corresponding to distinct transcriptomic states and functions: (1) nonpolar cells show differentiation and therapy sensitivity, (2) elongated cells are invasive, and (3) multipolar cells form intercellular networks. Importantly, chemoresistance is morphoclass-specific: elongated GSCs depend on YAP/TEAD1 signaling, while multipolar GSCs rely on gap junction-mediated networks. Targeting these vulnerabilities with specific inhibitors sensitized resistant GSC morphoclasses to temozolomide (TMZ) in patient-derived organoids. Our findings demonstrate that morphology provides critical insights into GSC behavior and establish a rationale for morphology-informed therapies to overcome resistance and improve outcomes in GBM. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=85 SRC="FIGDIR/small/644884v2_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@141e698org.highwire.dtl.DTLVardef@18a238corg.highwire.dtl.DTLVardef@23ef62org.highwire.dtl.DTLVardef@1390c07_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2024

Morphoregulatory ADD3 underlies glioblastoma growth and formation of tumor-tumor connections

Glioblastoma is a major unmet clinical need characterized by striking inter- and intra-tumoral heterogeneity and a population of glioblastoma stem cells (GSCs), conferring aggressiveness and therapy resistance. GSCs communicate through a network of tumor-tumor connections (TTCs), including nanotubes and microtubes, promoting tumor progression. However, very little is known about the mechanisms underlying TTC formation and overall GSC morphology. As GSCs closely resemble neural progenitor cells during neurodevelopment, we hypothesised that GSCs morphological features affect tumour progression. We identified GSC morphology as a new layer of tumoral heterogeneity with important consequences on GSC proliferation. Strikingly, we showed that the neurodevelopmental morphoregulator ADD3, is sufficient and necessary for maintaining proper GSC morphology, TTC abundance and cell cycle progression as well as required for cell survival. Remarkably, both the effects on cell morphology and proliferation depend on the stability of actin cytoskeleton. Hence, cell morphology and its regulators play a key role in tumor progression by mediating cell-cell communication. We thus propose that GSC morphological heterogeneity holds the potential to identify new therapeutic targets and diagnostic markers.

cell biology↗

bioRxiv2023

Structural mechanism of HP1-dependent transcriptional repression and chromatin compaction

Heterochromatin protein 1 (HP1) plays a central role in establishing and maintaining constitutive heterochromatin. However, the mechanisms underlying HP1-nucleosome interactions and their contributions to heterochromatin functions remain elusive. In this study, we employed a multidisciplinary approach to unravel the interactions between human HP1 and nucleosomes. We have elucidated the cryo-EM structure of an HP1 dimer bound to an H2A.Z nucleosome, revealing that the HP1 dimer interfaces with nucleosomes at two distinct sites. The primary binding site is located at the N-terminus of histone H3, specifically at the trimethylated K9 (K9me3) region, while a novel secondary binding site is situated near histone H2B, close to nucleosome superhelical location 4 (SHL4). Our biochemical data further demonstrates that HP1 binding influences the dynamics of DNA on the nucleosome. It promotes DNA unwrapping near the nucleosome entry and exit sites while concurrently restricting DNA accessibility in the vicinity of SHL4. This study offers a model that explains how HP1 functions in heterochromatin maintenance and gene silencing, particularly in the context of H3K9me-dependent mechanisms. Additionally, it sheds light on the H3K9me-independent role of HP1 in responding to DNA damage.

biochemistry↗

bioRxiv2022

Acute Cytomegalovirus Infection Modulates the Intestinal Microbiota and Targets Intestinal Epithelial Cells

Primary and recurrent cytomegalovirus (CMV) infections frequently cause CMV colitis in immunocompromised as well as inflammatory bowel disease (IBD) patients. Additionally, colitis occasionally occurs upon primary CMV infection in patients who are apparently immunocompetent. In both cases, the underlying pathophysiologic mechanisms are largely elusive - in part due to the lack of adequate access to specimens. We employed the mouse cytomegalovirus (MCMV) model to probe into the association between CMV and colitis. During acute primary MCMV infection of immunocompetent mice, the gut microbial composition was affected within the first 5 days post-infection as manifested by an altered ratio of the Firmicutes to Bacteroidetes phyla. Interestingly, these microbial changes incited with high-titer MCMV replication in the colon, mild crypt necrosis and increased colonic pro-inflammatory cytokine levels. Further analyses revealed that murine and human intestinal epithelial cell line as well as primary intestinal crypt cells/ organoids represent direct targets of CMV accompanied by increased cell mortality upon infection. Accordingly, in vivo MCMV infection disrupted the intestinal epithelial barrier and increased apoptosis of intestinal epithelial cells. In summary, our data show that CMV induces colitis in immunocompetent hosts by altering the intestinal homeostasis.

microbiology↗