Genomic Organization Research Articles

Pseudorabies virus as a zoonosis: scientific and public health implications.

Pseudorabies virus (PRV) is a herpes virus, also known as Aujeszky's disease virus (ADV), which can cause a highly infectious disease pseudorabies (PR) in a variety of mammals. In the past, it has been debated whether PRV can infect humans, but more and more cases of PRV infection have been reported since 2017. The illness has claimed many victims and left survivors with serious sequelae. This indicates that humans may ignore the zoonotic ability of PRV. This review aims to summarize the pathology and pathogenesis of PRV and speculate on how it infects humans. This paper provides a comprehensive overview of the progression of PRV, including its virology characteristics, genomic organization, and genetic evolution. It also synthesises the existing literature on PRV infection in humans, and analyses the factors contributing to PRV zoonosis. Finally, the pathogenesis of PRV-infected pigs and other mammals was summarized, and the pathogenesis of PRV-infected humans was speculated.

Genome Studies in Amaranthus cruentus L. and A. hypochondriacus L. Based on Repeatomic and Cytogenetic Data

Amaranthus cruentus L. and Amaranthus hypochondriacus L. are valuable and promising food crops for multi-purpose use that are distributed worldwide in temperate, subtropical, and tropical zones. However, their karyotypes and genomic relationships still remain insufficiently studied. For the first time, a comparative repeatome analysis of A. cruentus and A. hypochondriacus was performed based on the available NGS data; bioinformatic analyses using RepeatExplorer/TAREAN pipelines; and chromosome FISH mapping of 45S rDNA, 5S rDNA, and the most abundant satellite DNAs. In the repeatomes of these species, interspecific variations in the amount of Ty3/Gypsy and Ty1/Copia retroelements, DNA transposons, ribosomal, and satellite DNA were detected. In the repeatomes of both species, shared satDNAs with high sequence similarity were identified. The chromosome distribution patterns of four effective molecular markers, 45S rDNA, 5S rDNA, AmC4, and AmC9, allowed us to identify all chromosome pairs in the species karyotypes, construct unique karyograms of A. cruentus and A. hypochondriacus, and confirm the close relationship between their genomes. These results are important for comparative karyotypic studies within the genus Amaranthus. Our findings demonstrated that cytogenomic analyses might provide important data on genomic relationships within Amaranthus and increase knowledge on genome organization in these valuable crops.

Nucleosome fibre topology guides transcription factor binding to enhancers.

Cellular identity requires the concerted action of multiple transcription factors (TFs) bound together to enhancers of cell-type-specific genes. Despite TFs recognizing specific DNA motifs within accessible chromatin, this information is insufficient to explain how TFs select enhancers1. Here we compared four different TF combinations that induce different cell states, analysing TF genome occupancy, chromatin accessibility, nucleosome positioning and 3D genome organization at the nucleosome resolution. We show that motif recognition on mononucleosomes can decipher only the individual binding of TFs. When bound together, TFs act cooperatively or competitively to target nucleosome arrays with defined 3D organization, displaying motifs in particular patterns. In one combination, motif directionality funnels TF combinatorial binding along chromatin loops, before infiltrating laterally to adjacent enhancers. In other combinations, TFs assemble on motif-dense and highly interconnected loop junctions, and subsequently translocate to nearby lineage-specific sites. We propose a guided-search model in which motif grammar on nucleosome fibres acts as signpost elements, directing TF combinatorial binding to enhancers.

Vesicular Stomatitis Virus: Insights into Pathogenesis, Immune Evasion, and Technological Innovations in Oncolytic and Vaccine Development

Vesicular stomatitis virus (VSV) represents a significant advancement in therapeutic medicine, offering unique molecular and cellular characteristics that make it exceptionally suitable for medical applications. The bullet-shaped morphology, RNA genome organization, and cytoplasmic replication strategy provide fundamental advantages for both vaccine development and oncolytic applications. VSV’s interaction with host cells through the low-density lipoprotein receptor (LDL-R) and its sophisticated transcriptional regulation mechanisms enables precise control over therapeutic applications. The virus demonstrates remarkable versatility through its rapid replication cycle, robust immune response induction, and natural neurotropism. Recent technological innovations in VSV engineering have led to enhanced safety protocols and improved therapeutic modifications, particularly in cancer treatment. Attenuation strategies have successfully addressed safety concerns while maintaining the therapeutic efficacy of the virus. The molecular and cellular interactions of VSV, particularly its immune modulation capabilities and tumor-selective properties, have proven valuable in the development of targeted therapeutic strategies. This review explores these aspects, while highlighting the continuing evolution of VSV-based therapeutic approaches in precision medicine.

Development of patient-derived lymphomoids with preserved tumor architecture for lymphoma therapy screening

The efficacy of anti-cancer therapies depends on the genomic composition of the tumor, its microenvironment, spatial organization, and intra-tumor heterogeneity. B-cell lymphomas are a heterogeneous group of tumors emerging from B-cells at different stages of differentiation and exhibiting tumor-specific interactions with the tumor microenvironment. Thus, the effect of drug treatments can be influenced by the tumor composition and functional interactions among immune cells. Here, we develop a platform to maintain small fragments of human lymphoma tissue in culture for several days, and use them to test response to small molecules. We collect 27 patient samples representative of different lymphoma subtypes, and establish ex vivo tissue fragments that retain histological, cellular, and molecular characteristics of the original tissue, here referred to as lymphomoids. Using lymphomoids, we test sensitivity to several clinically approved drugs in parallel and examine tissue remodeling upon treatment. Moreover, when this information is available, we show that the effect of the inhibitors observed in lymphomoids is consistent with the patients’ response in the clinic. Thus, lymphomoids represent an innovative ex vivo model to assess the effect of anti-cancer therapies while preserving the tissue structure and its components.

Synergistic efficacy of phage Henu10 with antibiotics against Shigella dysenteriae with insight into phage resistance and fitness trade-offs

IntroductionThe irrational use of antibiotics has facilitated the emergence of multidrug- resistant Shigella spp., undermining the effectiveness of the currently available antibiotics. Consequently, there is an urgent need to explore new approaches, with phage therapy emerging as a promising alternative.MethodsIn this study, we isolated a phage targeting Shigella dysenteriae from sewage samples using DLA methold, designated Henu10. The morphology, biological characteristics, genomic composition, and phylogenetic relationships of Henu10 were thoroughly characterized. To investigate the trade-off relationship between phage resistance and bacterial fitness, phage Henu10-resistant strains R6 and R11 were identified using continuous passage and bidirectional validation methods.ResultsPhage-resistant strains R6 and R11 exhibited impaired adsorption, increased sensitivity to temperature and pH stress, heightened susceptibility to certain antibiotics (such as ciprofloxacin and kanamycin), reduced biofilm-forming capacity, and diminished colonization ability in vivo compared to the wild-type strain.DiscussionThese results indicate that phage Henu10 may effectively control the pathogenic bacteria associated with S. dysenteriae, representing a promising new therapeutic option for treating S. dysenteriae infections.

The complete chloroplast genome of a centennial olive tree (Olea europaea, Oleaceae) from the southern Peruvian coast

Olive (Olea europaea Linaeus 1753) is one of the valuable fruit trees and very important edible oil plant in the world. The chloroplast (cp) genome of an olive tree (Olea europaea) from the southern Peruvian arid coast was obtained for the first time. Genomic DNA of high quality was used to generate librarieswith Illumina Hiseq paired-end methods. The cp genome is 155,886 pb in length and contains a large single-copy region (LSC) of 86,610 pb and a small single copy region (SSC) of 17,790 pb separated by two inverted repeat (IR) regions (25,741bp). The cp genome of olive contains 124 genes that consists of 80 protein-coding genes, 36 tRNA, eight rRNA. Phylogenetic analysis showed this olive tree is sister to O. europaea subsp. maroccana (Oleeae tribe). This study presents the first overview of the chloroplast genome organization and phylogenetics of O. europaea, offering valuable insights for genetic and evolutionary research in the genus Olea.

Recent Crop-To-Weed Adaptive Introgression Has Reshaped the Genomic Composition and Geographical Structure of US Weedy Rice (Oryza spp.).

Weedy rice is a close relative of cultivated rice (Oryza sativa) that infests rice fields worldwide and drastically reduces yields. To combat this agricultural pest, rice farmers in the southern US began to grow herbicide-resistant (HR) rice cultivars in the early 2000s, which permitted the application of herbicides that selectively targeted weedy rice without harming the crop. The widespread adoption of HR rice coincided with increased reliance on hybrid rice cultivars in place of traditional inbred varieties. Although both cultivated and weedy rice are predominantly self-fertilising, the combined introductions of HR and hybrid rice dramatically altered the opportunities and selective pressure for crop-weed hybridization and adaptive introgression. In this study, we generated genotyping-by-sequencing data for 178 weedy rice samples collected from across the rice growing region of the southern US; these were analysed together with previously published rice and weedy rice genome sequences to determine the recent genomic and population genetic consequences of adaptive introgression and selection for herbicide resistance in US weedy rice populations. We find a reshaped geographical structure of southern US weedy rice as well as purging of crop-derived alleles in some weed strains of crop-weed hybrid origin. Furthermore, we uncover evidence that related weedy rice strains have made use of different genetic mechanisms to respond to selection. Lastly, we identify widespread presence of HR alleles in both hybrid-derived and nonadmixed samples, which further supports an overall picture of weedy rice evolution and adaptation through diverse genetic mechanisms.

Gene mobility elements mediate cell type specific genome organization and radial gene movement in vivo.

Understanding the level of genome organization that governs gene regulation remains a challenge despite advancements in chromatin profiling techniques. Cell type specific chromatin architectures may be obscured by averaging heterogeneous cell populations. Here we took a reductionist perspective, starting with the relocation of the hunchback gene to the nuclear lamina in Drosophila neuroblasts. We previously found that this event terminates competence to produce early-born neurons and is mediated by an intronic 250 base-pair element, which we term gene mobility element (GME). Here we found over 800 putative GMEs globally that are chromatin accessible and are Polycomb (PcG) target sites. GMEs appear to be distinct from PcG response elements, however, which are largely chromatin inaccessible in neuroblasts. Performing in situ Hi-C of purified neuroblasts, we found that GMEs form megabase-scale chromatin interactions, spanning multiple topologically associated domain borders, preferentially contacting other GMEs. These interactions are cell type and stage-specific. Notably, GMEs undergo developmentally- timed mobilization to/from the neuroblast nuclear lamina, and domain swapping a GFP reporter transgene intron with a GME relocates the transgene to the nuclear lamina in embryos. We propose that GMEs constitute a genome organizational framework and mediate gene-to-lamina mobilization during progenitor competence state transitions in vivo .

Loop-extrusion-mediated plasmid DNA cleavage by the bacterial SMC Wadjet complex.

Structural maintenance of chromosomes (SMC) complexes play pivotal roles in genome organization and maintenance across all domains of life. In prokaryotes, SMC-family Wadjet complexes structurally resemble the widespread MukBEF but serve a defensive role by inhibiting plasmid transformation. We previously showed that Wadjet specifically cleaves plasmid DNA; however, the molecular mechanism underlying plasmid recognition remains unclear. Here, we use invitro single-molecule imaging to directly visualize DNA loop extrusion and plasmid cleavage by Wadjet. We find that Wadjet is a symmetric loop extruder that simultaneously reels in DNA from both sides of a loop and that this activity requires a dimeric JetABC supercomplex. On surface-anchored plasmid DNAs, Wadjet extrudes the full length of a 44-kb-pair plasmid, stalls, and cleaves DNA. Our findings reveal the role of loop extrusion in the specific recognition and elimination of plasmids by Wadjet and establish loop extrusion as an evolutionarily conserved mechanism among SMC complexes across all kingdoms of life.

Comparative Analysis of Mitogenomes in Leafhopper Tribe Deltocephalini (Hemiptera: Cicadellidae: Deltocephalinae): Structural Conservatism and Phylogeny

ABSTRACTPrevious studies on the gene order and composition of leafhopper mitochondrial genomes have revealed a high level of conservation in overall genome structure. Some members of Deltocephalinae, the largest subfamily, exhibit tRNA gene rearrangements; however, few mitogenomes have been sequenced in this group and the degree of structural variation within tribes remains unclear. In this study, we sequenced the complete mitogenomes of 14 species belonging to four genera of tribe Deltocephalini from China and compared them with the two previously reported mitogenomes for this tribe. The studied mitogenomes showed a high degree of similarity to most other leafhopper mitogenomes in overall structure, mostly varying in the total length (14,961–15,416 bp) and number of non‐coding A + T‐rich regions. Gene size, order, arrangement, base composition, codon usage, and secondary structure of tRNAs in the newly sequenced mitogenomes were highly conserved in Deltocephalini, and variations in start/stop codon usage and tRNA secondary structure mostly matched those of other leafhoppers. Phylogenetic analysis of different combinations of protein‐coding and ribosomal genes using maximum likelihood and Bayesian inference under different models using either amino acid or nucleotide sequences were generally consistent and agreed with the previous nuclear and partial mitochondrial gene sequence data, indicating that complete mitochondrial genomes are phylogenetically informative at different levels of divergence within Deltocephalini and among different leafhoppers species. In addition to Deltocephalini, Deltocephalinae included members of Athysanini and Opsiini formed monophyletic groups. Maximum likelihood and Bayesian inference analyses consistently grouped Graminella nigrinota with Paralimnini, rendering Deltocephalini polyphyletic. The topology consistently divided Deltocephalini into two major branches, with Alobaldia tobae and Polyamia penistenuis forming a well‐supported sister group to the remaining species of the tribe.

Characterization of radiations‐induced genomic structural variations in Arabidopsis thaliana

SUMMARYDNA, is assaulted by endogenous and exogenous agents that lead to the formation of damage. In order to maintain genome integrity DNA repair pathways must be efficiently activated to prevent mutations and deleterious chromosomal rearrangements. Conversely, genome rearrangement is also necessary to allow genetic diversity and evolution. The antagonist interaction between maintenance of genome integrity and rearrangements determines genome shape and organization. Therefore, it is of great interest to understand how the whole linear genome structure behaves upon formation and repair of DNA damage. For this, we used long reads sequencing technology to identify and to characterize genomic structural variations (SV) of wild‐type Arabidopsis thaliana somatic cells exposed either to UV‐B, to UV‐C or to protons irradiations. We found that genomic regions located in heterochromatin are more prone to form SVs than those located in euchromatin, highlighting that genome stability differs along the chromosome. This holds true in Arabidopsis plants deficient for the expression of master regulators of the DNA damage response (DDR), ATM (Ataxia‐telangiectasia‐mutated) and ATR (Ataxia‐telangiectasia‐mutated and Rad3‐related), suggesting that independent and alternative surveillance processes exist to maintain integrity in genic regions. Finally, the analysis of the radiations‐induced deleted regions allowed determining that exposure to UV‐B, UV‐C and protons induced the microhomology‐mediated end joining mechanism (MMEJ) and that both ATM and ATR repress this repair pathway.

A catalog of gene editing sites and genetic variations in editing sites in model organisms

BackgroundCRISPR-Cas systems require a protospacer adjacent motif (PAM), which plays an essential role in self/non-self discrimination in their natural context, to cleave DNA for genome editing. Unfortunately, common genetic variation is distributed throughout genomes, which can block recognition of target sites by Cas proteins. However, little information is available about the distribution of editing sites in model organisms and how often common variation overlaps with those PAM sites.ResultsHerein, we characterized six representative Cas proteins (Cas9, Cas12a, Cas12b, Cas12i, Cas12j and Cas12l) genomic editing sites in ten model organisms (yeast, flatworms, flies, zebrafish, mice, humans, rice, maize, Arabidopsis and tomato). We demonstrated that there were more than 34 editing sites per kilobase on average in these genomes. In each genome, 91.69–99.83% and 95.4–99.73% of genes had at least one unique editing site in exon and promoter, respectively. Depending on publicly available genomic diversity data, we identified the variations (SNPs and InDels) in editing sites in humans and rice, indicating the risk in the application of CRISPR/Cas technology. Finally, using CCR5 and BCL11A as examples, we revealed variation site was a factor that must be considered when designing sgRNA.ConclusionsOur findings not only revealed the distribution characteristics of editing sites of six representative Cas proteins in ten model organism genomes but also shed light on the adverse effect of variation sites on target site recognition. Our current work will serve as a reminder of the risks of CRISPR application.

Evolutionary plasticity in nematode Hox gene complements and genomic loci arrangement

Hox genes are central to metazoan body plan formation, patterning and evolution, playing a critical role in cell fate decisions early in embryonic development in invertebrates and vertebrates. While the archetypical Hox gene cluster consists of members of nine ortholog groups (HOX1-HOX9), arrayed in close linkage in the order in which they have their anterior-posterior patterning effects, nematode Hox gene sets do not fit this model. The Caenorhabditis elegans Hox gene set is not clustered and contains only six Hox genes from four of the ancestral groups. The pattern observed in C. elegans is not typical of the phylum, and variation in orthologue set presence and absence and in genomic organisation has been reported. Recent advances in genome sequencing have resulted in the availability of many novel genome assemblies in Nematoda, especially from taxonomic groups that had not been analysed previously. Here, we explored Hox gene complements in high-quality genomes of 80 species from all major clades of Nematoda to understand the evolution of this key set of body pattern genes and especially to probe the origins of the “dispersed” cluster observed in C. elegans. We also included the recently available high-quality genomes of some Nematomorpha as an outgroup. We find that nematodes can have Hox genes from up to six orthology groups. While nematode Hox “clusters” are often interrupted by unrelated genes we identify species in which the cluster is intact and not dispersed.

Examining the molecular clock hypothesis for the contemporary evolution of the rabies virus.

The molecular clock hypothesis assumes that mutations accumulate on an organism's genome at a constant rate over time, but this assumption does not always hold true. While modelling approaches exist to accommodate deviations from a strict molecular clock, assumptions about rate variation may not fully represent the underlying evolutionary processes. There is considerable variability in rabies virus (RABV) incubation periods, ranging from days to over a year, during which viral replication may be reduced. This prompts the question of whether modelling RABV on a per infection generation basis might be more appropriate. We investigate how variable incubation periods affect root-to-tip divergence under per-unit time and per-generation models of mutation. Additionally, we assess how well these models represent root-to-tip divergence in time-stamped RABV sequences. We find that at low substitution rates (<1 substitution per genome per generation) divergence patterns between these models are difficult to distinguish, while above this threshold differences become apparent across a range of sampling rates. Using a Tanzanian RABV dataset, we calculate the mean substitution rate to be 0.17 substitutions per genome per generation. At RABV's substitution rate, the per-generation substitution model is unlikely to represent rabies evolution substantially differently than the molecular clock model when examining contemporary outbreaks; over enough generations for any divergence to accumulate, extreme incubation periods average out. However, measuring substitution rates per-generation holds potential in applications such as inferring transmission trees and predicting lineage emergence.

Long-read DNA sequencing reveals the organization of the mitochondrial genome in the early-branching dinoflagellate Oxyrrhis marina.

The mitochondrial genomes of dinoflagellate protists are remarkable for their highly fragmented and heterogeneous organization. Early attempts to determine their structure without ‘next-generation’ DNA sequencing failed to recover a defined genome. Still, it coincided in showing that the proteins coding genes, three in total, and parts of the ribosomal RNA genes were spread across a diffuse assortment of small linear fragments. In contrast, a recent study employed Illumina sequencing to assemble a 326 kbp long single-molecule, circular mitochondrial genome in the symbiotic dinoflagellate Breviolum minutum. Here, we used a combination of short- and long-read massively-parallel DNA sequencing to analyze further the mitochondrial DNA of the early-branching dinoflagellate Oxyrrhis marina. We found that the mitochondrial genome of O. marina consists of 3 linear chromosomes sized 15.9, 33.8 and 40.6 kbp for a total of 90.3 kbp. It contains the cox1, cox3 and cob genes, the same three proteins encoded in the mitochondrion of all myzozoans (Apicomplexa and Dinophyceae), some fragments of ribosomal RNA genes as well as many non-functional gene fragments and extensive noncoding DNA. Our analysis unveiled segments syntenic patterns and rearrangements encompassing coding and non-coding regions, suggesting that recombination is a pervasive process driving the evolution of these genomes.

Deciphering the ABA and GA biosynthesis approach of Bacillus pumilus, mechanistic approach, explaining the role of metabolic region as an aid in improving the stress tolerance

Bacillus pumilus plays an essential role in agricultural applications as a beneficial microbe and for sustainable agriculture production. However, the underlying mechanisms of B. pumilus strains remain unclear as to how they are beneficial for plants as stress tolerant and growth promoters. Bacillus pumilus was isolated from the rhizosphere soil of Artemisia vulgaris. NGS (next-generation sequencing) was performed for the strain to gain new insights into the molecular mechanisms underlying plant-microbial interactions. NGS revealed 3,910 genes, 3294 genes with protein-coding, and 11 functional genomic regions related to diverse agronomic traits including stress tolerance. We identified the two possible phytohormone biosynthesis approaches from metabolic regions1(terpense→diterpense→betacarotene→xanthoxin→ABA)2(terpense→diterpense→geranyl diphosphate →C20 →GA). Several gene clusters related to the biosynthesis of phytohormones, stress tolerance, and agricultural diversification were predicted. The genome provides insights into the possible mechanisms of this bacterium for stress tolerance and its future applications. The genomic organization of B. pumilus revealed several hallmarks of its plant growth promotion and pathogen suppression activities. Our results provide detailed genomic information for the strain and reveal its potential stress tolerance mechanisms, laying the foundation for developing effective stress tolerance strategies against abiotic stress.

The chromatin landscape of the histone-possessing Bacteriovorax bacteria.

Histone proteins have traditionally been thought to be restricted to eukaryotes and most archaea, with eukaryotic nucleosomal histones deriving from their archaeal ancestors. In contrast, bacteria lack histones as a rule. However, histone proteins have recently been identified in a few bacterial clades, most notably the phylum Bdellovibrionota, and these histones have been proposed to exhibit a range of divergent features compared to histones in archaea and eukaryotes. However, no functional genomic studies of the properties of Bdellovibrionota chromatin have been carried out. In this work, we map the landscape of chromatin accessibility, active transcription and three-dimensional genome organization in a member of Bdellovibrionota (a Bacteriovorax strain). We find that, similar to what is observed in some archaea and in eukaryotes with compact genomes such as yeast, Bacteriovorax chromatin is characterized by preferential accessibility around promoter regions. Similar to eukaryotes, chromatin accessibility in Bacteriovorax positively correlates with gene expression. Mapping active transcription through single-strand DNA (ssDNA) profiling revealed that unlike in yeast, but similar to the state of mammalian and fly promoters, Bacteriovorax promoters exhibit very strong polymerase pausing. Finally, similar to that of other bacteria without histones, the Bacteriovorax genome exists in a three-dimensional (3D) configuration organized by the parABS system along the axis defined by replication origin and termination regions. These results provide a foundation for understanding the chromatin biology of the unique Bdellovibrionota bacteria and the functional diversity in chromatin organization across the tree of life.

Comparative study of the three-dimensional genomes of granulosa cells in germinal vesicle and metaphase II follicles.

Follicle development is a critical process in the female reproductive system, with significant implications for fertility and reproductive health. Germinal vesicle (GV) oocytes are primary oocytes that are arrested in the dictyate stage, also known as the diplotene stage of meiotic prophase I. Metaphase II (MII) is the stage at which the oocyte is typically retrieved for assisted reproductive technologies such as in vitro fertilization (IVF). The granulosa cells play a pivotal role in follicle development processes. 3D chromatin organization is a fundamental aspect of cellular biology that has significant implications for gene regulation and cellular function. In this study, we investigated 3D chromatin organization in granulosacells from GV and MII follicles, which is essential for understanding the regulatory mechanisms governing oocyte development. The results revealed distinct compartmentalization patterns,including stable genomic regions and transitions during oocyte maturation. Notably, there was a significant shift in functional gene activation, particularly in processes related to hormone metabolic pathways. Furthermore, alterations in topologically associating domains (TADs) were observed, with differential expression observed in genes that are involved in crucial biological processes. The analysis also identified a subset of genes with altered promoter-enhancer interactions (PEIs), reflecting a regulatory shift in gene expression related to reproductive processes. These findings provide valuable insights into 3D genome organization in granulosa cells with implications for reproductive health and the development of assisted reproductive technologies. Understanding spatial genome organization at different stages of follicular development may help realize novel strategies for enhancing success rates in assisted reproductive technologies.

Disorganized chromatin hierarchy and stem cell aging in a male patient of atypical laminopathy-based progeria mandibuloacral dysplasia type A

Studies of laminopathy-based progeria offer insights into aging-associated diseases and highlight the role of LMNA in chromatin organization. Mandibuloacral dysplasia type A (MAD) is a largely unexplored form of atypical progeria that lacks lamin A post-translational processing defects. Using iPSCs derived from a male MAD patient carrying homozygous LMNA p.R527C, premature aging phenotypes are recapitulated in multiple mesenchymal lineages, including mesenchymal stem cells (MSCs). Comparison with 26 human aging MSC expression datasets reveals that MAD-MSCs exhibit the highest similarity to senescent primary human MSCs. Lamina-chromatin interaction analysis reveals reorganization of lamina-associating domains (LADs) and repositioning of non-LAD binding peaks may contribute to the observed accelerated senescence. Additionally, 3D genome organization further supports hierarchical chromatin disorganization in MAD stem cells, alongside dysregulation of genes involved in epigenetic modification, stem cell fate maintenance, senescence, and geroprotection. Together, these findings suggest LMNA missense mutation is linked to chromatin alterations in an atypical progeroid syndrome.