Biology subjects

Khrameeva, E. E.

Publications and source records attributed to Khrameeva, E. E..

8 recordsLinked to original sources

bioRxiv2025

Somatic mutations impose an entropic upper bound on human lifespan

Somatic mutations accumulate with age and can cause cell death, but their quantitative contribution to limiting human lifespan remains unclear. We developed an incremental modeling framework that progressively incorporates factors contributing to aging into a model of population survival dynamics, which we used to estimate lifespan limits if all aging hallmarks were eliminated except somatic mutations. Our analysis reveals fundamental asymmetry across organs: post-mitotic cells such as neurons and cardiomyocytes act as critical longevity bottlenecks, with somatic mutations reducing median lifespan from a theoretical non-aging baseline of 430 years to 169 years. In contrast, proliferating tissues like liver maintain functionality for thousands of years through cellular replacement, effectively neutralizing mutation-driven decline. Multi-organ integration predicts median lifespans of 134-170 years --approximately twice current human longevity. This substantial yet incomplete reduction indicates that somatic mutations significantly drive aging but cannot alone account for observed mortality, implying comparable contributions from other hallmarks.

systems biology↗

bioRxiv2025

The Divergent 3D Genome Landscapes of Aging and Neurodegenerative mouse models

Chromatin structure is essential for gene regulation and genome stability, and neurons must preserve their 3D genome organization throughout life. This structure gradually deteriorates with aging and is further disrupted in neurodegenerative diseases. To investigate whether aging and neurodegeneration share early chromatin changes or diverge, we performed Hi-C on cortical neurons from adult, aged, and brain-specific SIRT6-knockout (S6-KO) mice, and compared them to the CK-p25 Alzheimers disease model results stratified by {gamma}H2AX levels. All models showed early features such as weakened interactions between chromosomes in expanded nuclei, A-to-B compartment shifts, and loss of architectural loops. However, aged neurons retained TAD prominence, short-range interactions, and enhancer-promoter loops, while pathological models showed reduced TAD prominence, shorter loops, and disorganized A-B mixing. These changes correlate with increased DNA damage. Our findings suggest that aging represents a "primed" state, where chromatin regulation begins to erode, but further stressors like DNA damage are associated with progression toward neurodegenerative breakdown.

molecular biology↗

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

ComputAgeBench: Epigenetic Aging Clocks Benchmark

The success of clinical trials of longevity drugs relies heavily on identifying integrative health and aging biomarkers, such as biological age. Epigenetic aging clocks predict the biological age of an individual using their DNA methylation profiles, commonly retrieved from blood samples. However, there is no standardized methodology to validate and compare epigenetic clock models as yet. We propose ComputAgeBench, a unifying framework that comprises such a methodology and a dataset for comprehensive benchmarking of different clinically relevant aging clocks. Our methodology exploits the core idea that reliable aging clocks must be able to distinguish between healthy individuals and those with aging-accelerating conditions. Specifically, we collected and harmonized 66 public datasets of blood DNA methylation, covering 19 such conditions across different ages, and tested 13 published clock models. Additionally, we compiled 46 separate datasets to facilitate the training of new aging clocks. We believe our work will bring the fields of aging biology and machine learning closer together for the research on reliable biomarkers of health and aging. Codehttps://github.com/ComputationalAgingLab/ComputAge Datasethttps://huggingface.co/datasets/computage/computage_bench

bioinformatics↗

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↗

bioRxiv2020

Reduced purine biosynthesis in humans after their divergence from Neandertals

We analyze the metabolomes of humans, chimpanzees and macaques in muscle, kidney and three different regions of the brain. Whereas several compounds in amino acid metabolism occur at either higher or lower concentrations in humans than in the other primates, metabolites in oxidative phosphorylation and purine biosynthesis are consistently present in lower concentrations in the brains of humans. In particular, metabolites downstream of adenylosuccinate lyase, which catalyzes two reactions in purine synthesis, occur at lower concentrations in humans. This enzyme carries an amino acid substitution that is present in all humans today but absent in Neandertals. By introducing the modern human substitution into the genomes of mice, as well as the ancestral, Neandertal-like substitution into the genomes of human cells, we show that this amino acid substitution is responsible for much or all of the reduction of de novo synthesis of purines in humans.

evolutionary biology↗