Biology subjects

Razin, S. V.

Publications and source records attributed to Razin, S. V..

13 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↗

bioRxiv2024

Convergent gene pairs restrict chromatin looping in Dictyostelium discoideum, acting as directional barriers for extrusion

Dictyostelium discoideum is a unicellular slime mold, developing into a multicellular fruiting body upon starvation. Development is accompanied by large-scale shifts in gene expression program, but underlying features of chromatin spatial organization remain unknown. Here, we report that the Dictyostelium 3D genome is organized into positionally conserved, largely consecutive, non-hierarchical and weakly insulated loops at the onset of multicellular development. The transcription level within the loop interior tends to be higher than in adjacent regions. Loop interiors frequently contain functionally linked genes and genes which coherently change expression level during development. Loop anchors are predominantly positioned by the genes in convergent orientation. Our data suggest that the loop profile may arise from the interplay between transcription and extrusion-driven chromatin folding. In particular, a convergent gene pair serves as a bidirectional extrusion barrier or a "diode" that controls passage of the cohesin extruder by relative transcription level of paired genes.

molecular biology↗

bioRxiv2024

Long non-coding RNAs direct the SWI/SNF complex to cell-specific enhancers

The coordination of chromatin remodeling is essential for DNA accessibility and gene expression control1. The highly conserved and ubiquitously expressed SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex plays a central role in cell type- and context-dependent gene expression2. Despite the absence of a defined DNA recognition motif, SWI/SNF binds lineage specific enhancers genome-wide where it actively maintains open chromatin state2-5. It does so while retaining the ability to respond dynamically to cellular signals4. However, the mechanisms that guide SWI/SNF to specific genomic targets have remained elusive. Here we demonstrate that trans-acting long non-coding RNAs (lncRNAs) direct the SWI/SNF complex to cell type-specific enhancers. SWI/SNF preferentially binds lncRNAs and these predominantly bind DNA targets in trans. Together they localize to enhancers, many of which are cell type-specific. Knockdown of SWI/SNF- and enhancer-bound lncRNAs causes the genome-wide redistribution of SWI/SNF away from enhancers and a concomitant differential expression of spatially connected target genes. These lncRNA-SWI/SNF-enhancer networks support an enhancer hub model of SWI/SNF genomic targeting. Our findings reveal a competitive recruitment of SWI/SNF by lncRNAs which provide a specific and dynamic layer of control in chromatin accessibility and gene expression.

molecular biology↗

bioRxiv2023

Nucleoporin Elys attaches peripheral chromatin to the nuclear pores in interphase nuclei

Transport of macromolecules through the nuclear envelope (NE) is mediated by nuclear pore complexes (NPCs) consisting of nucleoporins (Nups). Elys/Mel-28 is the Nup that binds and connects the decondensing chromatin with the reassembled NPCs at the end of mitosis. Whether Elys links chromatin with the NE during interphase is unknown. Using DamID-seq, we identified Elys binding sites in Drosophila late embryos and divided them into those associated with nucleoplasmic or with NPC-linked Elys. These Elys binding sites are located within active or inactive chromatin, respectively. Strikingly, Elys knockdown in S2 cells results in peripheral chromatin displacement from the NE, in decondensation of NE-attached chromatin, and in derepression of genes within. It also leads to slightly more compact active chromatin regions. Our findings indicate that NPC-linked Elys, together with the nuclear lamina, anchors peripheral chromatin to the NE, whereas nucleoplasmic Elys decompacts active chromatin. Author summaryHeterochromatin in interphase nucleus is localized mostly at the nuclear periphery. However, the forces maintaining its peripheral localization are not well understood. Nuclear envelope consists of two lipid bilayer membranes separated by perinuclear space. The inner nuclear membrane is lined by the nuclear lamina, and both membranes are pierced by nuclear pore complexes composed of nucleoporins. Nuclear envelope can serve as a scaffold to which heterochromatin is attached. In the present study, we identified nucleoporin Elys as one of the key players maintaining peripheral localization of heterochromatin during interphase. Elys binds to multiple genomic sites located within heterochromatin and thus links it to nuclear pore complexes. However, the nucleoplasmic fraction of Elys binds to active genes and enhancers, resulting in decompactization of their chromatin.

genomics↗

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

Extrusion fountains are hallmarks of chromosome organization emerging upon zygotic genome activation

The initiation of gene expression during development, known as zygotic genome activation (ZGA), is accompanied by massive changes in chromosome organization. However, the earliest events of chromosome folding and their functional roles remain unclear. Using Hi-C on zebrafish embryos, we discovered that chromosome folding begins early in development with the formation of "fountains", a novel element of chromosome organization. Emerging preferentially at enhancers, fountains exhibit an initial accumulation of cohesin, which later redistributes to CTCF sites at TAD borders. Knockouts of pioneer transcription factors driving ZGA enhancers result in the specific loss of fountains, establishing a causal link between enhancer activation and fountain formation. Polymer simulations demonstrate that fountains may arise as sites of facilitated cohesin loading, requiring two-sided but desynchronized loop extrusion, potentially caused by cohesin collisions with obstacles or internal switching. Moreover, we detected similar fountain patterns at enhancers in mouse cells. Fountains disappear upon acute cohesin depletion, as well as during mitosis, and reappear with cohesin loading in early G1. Altogether, fountains represent the first known enhancer-specific elements of chromosome organization and constitute starting points for chromosome folding during development, likely through facilitated cohesin loading.

molecular biology↗

bioRxiv2023

Phase separation of Treacle is indispensable for ribosomal transcription and DNA repair.

We investigated the role of the nucleolar protein Treacle in organizing and regulating the nucleolus in human cells. Our results support Treacles ability to form liquid-like phase condensates through electrostatic interactions among molecules. The formation of these biomolecular condensates is crucial for segregating nucleolar fibrillar centers from the dense fibrillar component and ensuring high levels of rRNA gene transcription and accurate rRNA processing. Both the central and C-terminal domains of Treacle are required to form liquid-like condensates. The initiation of phase separation is attributed to the C-terminal domain. The central domain is characterized by repeated stretches of alternatively charged amino-acid residues and is vital for condensate stability. Overexpression of mutant forms of Treacle that cannot form liquid-like phase condensates compromises the assembly of fibrillar centers, suppressing rRNA gene transcription and disrupting rRNA processing. These mutant forms also fail to recruit DNA topoisomerase II binding protein 1 (TOPBP1), suppressing the DNA damage response in the nucleolus.

cell biology↗

bioRxiv2023

A genome-wide nucleosome-resolution map of promoter-centered interactions in human cells corroborates the enhancer-promoter looping model

The enhancer-promoter looping model, in which enhancers activate their target genes via physical contact, has long dominated the field of gene regulation. However, the ubiquity of this model has been questioned due to evidence of alternative mechanisms and the lack of its systematic validation, primarily owing to the absence of suitable experimental techniques. In this study, we present a new MNase-based proximity ligation method called MChIP-C, allowing for the measurement of protein-mediated chromatin interactions at single-nucleosome resolution on a genome-wide scale. By applying MChIP-C to study H3K4me3 promoter-centered interactions in K562 cells, we found that it had greatly improved resolution and sensitivity compared to restriction endonuclease-based C-methods. This allowed us to identify EP300 histone acetyltransferase and the SWI/SNF remodeling complex as potential candidates for establishing and/or maintaining enhancer-promoter interactions. Finally, leveraging data from published CRISPRi screens, we found that most functionally-verified enhancers do physically interact with their cognate promoters, supporting the enhancer-promoter looping model.

genomics↗

bioRxiv2021

3C-seq-captured chromosome conformation of the hyperthermophilic archaeon Thermofilum adornatum

Three-dimensional structure of chromosomes displays diverse patterns across the tree of life, with compartments, interaction domains and loops being quite universally observed. The archaeal kingdom remains understudied to this extent so far, despite representing an interesting area from evolutionary and other perspectives. Here we describe the spatial chromosomal organization of a hyperthermophilic crenarchaeon Thermofilum adornatum strain 1910b based on high-throughput chromosome conformation capture (3C-seq) approach. The chromosome contact map showed a curved secondary diagonal almost orthogonal to the main one. No evidence of chromosome loops was present. We were able to identify boundaries of different strengths between chromosome interaction domains (CIDs) albeit moderate. The plaid-like patterns previously reported for Sulfolobus archaea were not observed. However, the calculation of A/B compartments divided the genome into 2 domains that were different by the density of predicted highly expressed genes and location of origins. Further comparison of these domains with whole-genome gene expression profiles will allow to test whether these domains represent expression-associated compartments. If so, it is possible that they represent primitive compartments evolutionarily older than the plaid patterns of Sulfolobus and higher eukaryotes. Further exploration of 3D chromatin in all branches of archaeal diversity will elucidate the evolution of the links between structural and functional organization in live organisms.

bioinformatics↗

bioRxiv2020

Suppression of liquid-liquid phase separation by 1,6-hexanediol partially compromises the 3D genome organization in living cells

Liquid-liquid phase separation (LLPS) contributes to the spatial and functional segregation of molecular processes. However, the role played by LLPS in chromatin folding in living cells remains unclear. Here, using stochastic optical reconstruction microscopy (STORM) and Hi-C techniques, we studied the effects of 1,6-hexanediol (1,6-HD)-mediated LLPS modulation on higher-order chromatin organization in living cells. We found that 1,6-HD treatment caused the enlargement of nucleosome nanodomains and their more uniform distribution in the nuclear space. At a megabase-scale, chromatin underwent moderate but irreversible perturbations that resulted in the partial mixing of A and B compartments. The removal of 1,6-HD from the culture medium did not allow chromatin to acquire initial configurations, but increased further mixing of the chromatin compartments and resulted in more compact repressed chromatin than in untreated cells. 1,6-HD treatment also weakened enhancer-promoter interactions but did not considerably affect CTCF-dependent loops. Our results suggest that 1,6-HD-sensitive LLPS plays a limited role in chromatin spatial organization by constraining its folding patterns and facilitating compartmentalization at different levels.

molecular biology↗

bioRxiv2019

Studying RNA#8211;DNA interactome by Red-C identifies noncoding RNAs associated with repressed chromatin compartment and reveals transcription dynamics

Non-coding RNAs (ncRNAs) participate in various biological processes, including regulating transcription and sustaining genome 3D organization. Here, we present a method termed Red-C that exploits proximity ligation to identify contacts with the genome for all RNA molecules present in the nucleus. Using Red-C, we uncovered the RNA-DNA interactome of human K562 cells and identified hundreds of ncRNAs enriched in active or repressed chromatin, including previously undescribed RNAs. We found two microRNAs--MIR3648 and MIR3687 transcribed from the rRNA locus--that are associated with inactive chromatin genome wide. These miRNAs favor bulk heterochromatin over Polycomb-repressed chromatin and interact preferentially with late-replicating genomic regions. Analysis of the RNA-DNA interactome also allowed us to trace the kinetics of messenger RNA production. Our data support the model of co-transcriptional intron splicing, but not the hypothesis of the circularization of actively transcribed genes.

genomics↗