Biology subjects

Jeon, S.

Publications and source records attributed to Jeon, S..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

Mll4 regulates postnatal palate growth and midpalatal suture development

MLL4, also known as KMT2D, is a histone methyltransferase that acts as an important epigenetic regulator in various organogenesis programs. Mutations in the MLL4 gene are the major cause of Kabuki syndrome, a human developmental disorder that involves craniofacial birth defects, including anomalies in the palate. This study aimed to investigate the role of MLL4 and the underlying mechanisms in the development and growth of the palate. We generated a novel conditional knockout (cKO) mouse model with tissue-specific deletion of Mll4 in the palatal mesenchyme. Using micro-computed tomography (CT), histological analysis, cell mechanism assays, and gene expression profiling, we examined palate development and growth in the Mll4-cKO mice. Gross craniofacial examination at adult stages revealed mild midfacial hypoplasia and midline defects of the palate in Mll4-cKO mice, including a widened midpalatal suture and disrupted midline rugae pattern. Micro-CT-based time-course skeletal analysis during postnatal palatogenesis through adulthood demonstrated a transverse growth deficit in overall palate width in Mll4-cKO mice. Whole-mount and histological staining at perinatal stages identified that the midline defects in the Mll4-cKO mice emerged as early as one day prior to birth, presenting as a widened midpalatal suture, accompanied by increased cell apoptosis in the suture mesenchyme. Genome-wide mRNA expression analysis of the midpalatal suture tissue revealed that MLL4 is essential for the timely expression of major cartilage development genes, such as Col2a1 and Acan, at birth. Immunofluorescence staining for osteochondral differentiation markers demonstrated a marked decrease in the chondrogenic marker COL2A1, while the expression of the osteogenic marker RUNX2 remained unchanged, in the Mll4-cKO midpalatal suture. Additionally, SOX9, a master regulator of chondrogenesis, exhibited a significant decrease in protein expression. Indeed, time-course histological analysis during postnatal palate growth revealed retardation in the development of the suture cartilage in Mll4-cKO mice. Taken together, our results demonstrate that MLL4 is essential for orchestrating key cellular and molecular events that ensure proper midpalatal suture development and palate growth.

developmental biology↗

bioRxiv2024

Dokdo sea lion Zalophus japonicus genome reveals its evolutionary trajectory before extinction

BackgroundThe Dokdo sea lion (Zalophus japonicus), commonly referred to as Gangchi in Korea and known as the Japanese sea lion, was endemic to the Northwest Pacific coast before becoming extinct in the 1950s. Little is known about its origins, speciation compared to other Otariidae species or how the rapid decline affected the species genetic diversity. ResultsTo raise the Dokdo sea lion from this relative obscurity, we sequenced DNA from 16 Z. japonicus bone fragments, obtained from Dokdo and Ulleungdo islands in Korea. Our analysis establishes Z. japonicus as the earliest diverged species within its genus, significantly redefining its evolutionary relationship with the California (Z. californianus) and Galapagos (Z. wollebaeki) sea lions. This genome-scale analysis clarifies the phylogeny of Z. japonicus, shedding light on its speciation and the evolutionary pathways that shaped its genetic diversity before its extinction. In addition, we discovered, population decline of the Z. japonicus started already 1,000 years ago, however, Z. japonicus genome maintained a relatively high heterozygosity despite, nearing extinction. ConclusionsOur genome-scale analysis eliminated ambiguity in Z. japonicus phylogeny, and shed light on the evolutionary pathways underlying its speciation. This study highlights the importance of the genome-scale analysis for extinct species to understand their complex evolutionary histories and conservation status.

genomics↗

bioRxiv2024

Identification of 17 novel epigenetic biomarkers associated with anxiety disorders using differential methylation analysis followed by machine learning-based validation

BackgroundThe changes in DNA methylation patterns may reflect both physical and mental well-being, the latter being a relatively unexplored avenue in terms of clinical utility for psychiatric disorders. In this study, our objective was to identify the methylation-based biomarkers for anxiety disorders and subsequently validate their reliability. MethodsA comparative differential methylation analysis was performed on whole blood samples from 94 anxiety disorder patients and 296 control samples using targeted bisulfite sequencing. Subsequent validation of identified biomarkers employed an artificial intelligence- based risk prediction models: a linear calculation-based methylation risk score model and two tree-based machine learning models: Random Forest and XGBoost. Results17 novel epigenetic methylation biomarkers were identified to be associated with anxiety disorders. These biomarkers were predominantly localized near CpG islands, and they were associated with two distinct biological processes: 1) cell apoptosis and mitochondrial dysfunction and 2) the regulation of neurosignaling. We further developed a robust diagnostic risk prediction system to classify anxiety disorders from healthy controls using the 17 biomarkers. Machine learning validation confirmed the robustness of our biomarker set, with XGBoost as the best-performing algorithm, an area under the curve of 0.876. ConclusionOur findings support the potential of blood liquid biopsy in enhancing the clinical utility of anxiety disorder diagnostics. This unique set of epigenetic biomarkers holds the potential for early diagnosis, prediction of treatment efficacy, continuous monitoring, health screening, and the delivery of personalized therapeutic interventions for individuals affected by anxiety disorders.

bioinformatics↗

bioRxiv2024

A high-quality de novo genome assembly of Asian Crested Ibis (Nipponia Nippon) using long-read and Hi-C data

We present TtaoRef1, the highest-quality de novo genome assembly of Asian Crested Ibis (Nipponia Nippon) to date consisting of 134 scaffolds with a length of 1.25 Gb and N50 of 101,183,595 bp. This assembly was generated through the utilization of long-read sequencing and Hi-C data. The assessment of assembly quality, conducted via Benchmarking Universal Single-Copy Orthologs (BUSCO), revealed the presence of 96.8% of completely predicted single-copy genes. TtaoRef1 had 18 times longer N50 value than the previous assembly (ASM70822v1), Furthermore, we conducted the annotation of 24,681 protein-coding genes within the newly assembled genome sequences.

bioinformatics↗

bioRxiv2024

ACE1 knockout in neurons selectively dysregulates the hippocampal renin angiotensin system and causes vascular loss

Angiotensin I converting enzyme (ACE1) maintains blood pressure homeostasis by converting angiotensin I (angI) into angiotensin II (angII) in the renin-angiotensin system (RAS). ACE1 is expressed in the brain, where an intrinsic RAS regulates complex cognitive functions including learning and memory. ACE1 has been implicated in neurodegenerative disorders including Alzheimers disease (AD) and Parkinsons disease (PD), but the mechanisms remain incompletely understood. Here, we performed single-nucleus RNA sequencing to characterize the expression RAS genes in the hippocampus and discovered that Ace is mostly expressed in CA region excitatory neurons. To gain a deeper understanding of the function of neuronal ACE1, we generated ACE1 conditional knockout (cKO) mice lacking ACE1 expression specifically in hippocampal and cortical excitatory neurons. Interestingly, ACE1 cKO mice exhibited hippocampus-dependent memory impairment in the Morris water maze, y-maze, and fear conditioning tests, but exhibited normal motor skills in rotarod. Total ACE1 level was significantly reduced in the cortex and hippocampus of ACE1 cKO mice showing that excitatory neurons are the predominant cell type expressing ACE1 in the forebrain. Despite similar reductions in total ACE1 level in both the hippocampus and cortex, the RAS pathway was dysregulated in the hippocampus only. Importantly, ACE cKO mice exhibited exacerbated age-related capillary loss selectively in the hippocampus. Here, we show selective vulnerability of the hippocampal microvasculature and RAS pathway to neuronal ACE1 knockout. Our results provide important insights into the function of ACE1 in the brain and demonstrate a connection between neuronal ACE and cerebrovascular function in the hippocampus.

neuroscience↗

bioRxiv2023

1.7 GHz long-term evolution radiofrequency electromagnetic field with efficient thermal control has no effect on the proliferation of different human cell types

Long-term evolution (LTE) radiofrequency electromagnetic field (RF-EMF) is widely used in communication technologies. As a result, the influence of RF-EMF on biological systems is a major public concern, and its physiological effects remain controversial. In our previous study, we showed that continuous exposure of various human cell types to 1.7 GHz LTE RF-EMF at specific absorption rate (SAR) of 2 W/Kg for 72 h can induce cellular senescence. To understand the precise cellular effects of LTE RF-EMF, we elaborated the 1.7 GHz RF-EMF cell exposure system used in the previous study by replacing the RF signal generator and developing a software-based feedback system to improve the exposure power stability. This refinement of the 1.7 GHz LTE RF-EMF generator facilitated the automatic regulation of RF-EMF exposure, maintaining target power levels within a 3% range and a constant temperature even during the 72-h exposure period. With the improved experimental setup, we examined the effect of continuous exposure to 1.7 GHz LTE RF-EMF at up to SAR of 8 W/Kg of adipose tissue-derived stem cells and Huh7, HeLa, and B103 cells. Surprisingly, the proliferation of all cell types, which displayed different growth rates, did not change significantly compared with that of the unexposed controls. However, when the thermal control system was turned off and the subsequent temperature increase induced by the RF-EMF was not controlled during continuous exposure to SAR of 8 W/Kg LTE RF-EMF, cellular proliferation increased by 35.2% at the maximum. These observations strongly suggest that the cellular effects attributed to 1.7 GHz LTE RF-EMF exposure were primarily due to the induced thermal changes, rather than the RF-EMF exposure itself.

cell biology↗

bioRxiv2023

SKIN REINNERVATION BY COLLATERAL SPROUTING FOLLOWING SPARED NERVE INJURY IN MICE

Following peripheral nerve injury, denervated tissues can be reinnervated via regeneration of injured neurons or via collateral sprouting of neighboring uninjured afferents into the denervated territory. While there has been substantial focus on mechanisms underlying regeneration, collateral sprouting has received relatively less attention. In this study, we used immunohistochemistry and genetic neuronal labeling to define the subtype specificity of sprouting-mediated reinnervation of plantar hind paw skin in the mouse spared nerve injury (SNI) model, in which productive regeneration cannot occur. Following an initial loss of cutaneous afferents in the tibial nerve territory, we observed progressive centripetal reinnervation by multiple subtypes of neighboring uninjured fibers into denervated glabrous and hairy plantar skin. In addition to dermal reinnervation, CGRP-expressing peptidergic fibers slowly but continuously repopulated the denervated epidermis, Interestingly, GFR2-expressing nonpeptidergic fibers exhibited a transient burst of epidermal reinnervation, followed by trend towards regression. Presumptive sympathetic nerve fibers also sprouted into the denervated territory, as did a population of myelinated TrkC lineage fibers, though the latter did so less efficiently. Conversely, rapidly adapting A{beta} fiber and C fiber low threshold mechanoreceptor (LTMR) subtypes failed to exhibit convincing collateral sprouting up to 8 weeks after nerve injury. Optogenetics and behavioral assays further demonstrated the functionality of collaterally sprouted fibers in hairy plantar skin with restoration of punctate mechanosensation without hypersensitivity. Our findings advance understanding of differential collateral sprouting among sensory neuron subpopulations and may guide strategies to promote the progression of sensory recovery or limit maladaptive sensory phenomena after peripheral nerve injury. Significance StatementFollowing nerve injury, whereas one mechanism for tissue reinnervation is regeneration of injured neurons, another, less well studied mechanism is collateral sprouting of nearby uninjured neurons. In this study, we examined collateral sprouting in denervated mouse skin and showed that it involves some, but not all neuronal subtypes. Despite such heterogeneity, a significant degree of restoration of punctate mechanical sensitivity is achieved. These findings highlight the diversity of collateral sprouting among peripheral neuron subtypes and reveal important differences between pre- and post-denervation skin that might be appealing targets for therapeutic correction to enhance functional recovery from denervation and prevent unwanted sensory phenomena such as pain or numbness.

neuroscience↗

bioRxiv2023

Conservation implications of elucidating the Korean wolf taxonomic ambiguity through whole-genome sequencing

The taxonomic status of the now likely extirpated Korean Peninsula wolf has been extensively debated, with some arguing it represents an independent wolf lineage, Canis coreanus. To investigate the Korean wolf genetic affiliations and their taxonomic implications, we sequenced and analysed the genomes of a historical Korean wolf dated to the beginning of the 20th century, and a captive wolf originally located at the Pyongyang Central Zoo. Our results indicated that the Korean wolf bears similar genetic ancestry to other regional East Asian populations, therefore suggesting it is not a distinct taxonomic lineage. We identified regional patterns of wolf population structure and admixture in East Asia with potential conservation consequences in the Korean Peninsula and on a regional scale. We find the Korean wolf has similar diversity and inbreeding to other East Asian wolves. Finally, we show that, in contrast to the historical sample, the captive wolf is more genetically similar to wolves from the Tibetan Plateau, hence, Korean wolf conservation programs might not benefit from the inclusion of this specimen.

evolutionary biology↗

bioRxiv2022

Korea4K: whole genome sequences of 4,157 Koreans with 107 phenotypes derived from extensive health check-ups

We present 4,157 whole-genome sequences (Korea4K) coupled with 107 health check-up parameters as the largest whole genomic resource of Koreans. Korea4K provides 45,537,252 variants and encompasses most of the common and rare variants in Koreans. We identified 1,356 new geno-phenotype associations which were not found by the previous Korea1K dataset. Phenomics analyses revealed 24 genetic correlations, 1,131 pleiotropic variants, and 127 causal relationships from Mendelian randomization. Moreover, the Korea4K imputation reference panel showed a superior imputation performance to Korea1K. Collectively, Korea4K provides the most extensive genomic and phenomic data resources for discovering clinically relevant novel genome-phenome associations in Koreans.

genomics↗

bioRxiv2022

Ceramide synthase 6 (CerS6) promotes alcohol-induced fatty liver by promoting metabolic dysfunction and upregulating lipid droplet-associated proteins

ObjectiveAlcohol-associated liver disease (ALD) is the leading cause of liver-related mortality worldwide. Current strategies to manage ALD largely focus on advanced stage disease, however, metabolic changes such as glucose intolerance are apparent at the earliest stage of alcoholic steatosis and increase the risk of disease progression. Ceramides impair insulin signaling and accumulate in ALD, and metabolic pathways involving ceramide synthase 6 (CerS6) are perturbed in ALD during hepatic steatosis. In this study, we aimed to investigate the role of CerS6 in ALD development. MethodsC57BL/6 WT and CerS6 KO mice of both sexes were fed either a Lieber-DeCarli control (CON) or 15% ethanol (EtOH) diet for 6 weeks. In vivo metabolic tests including glucose and insulin tolerance tests (GTT and ITT) were performed. The mice were euthanized, and liver histology and lipid levels in serum and liver were measured. For in vitro studies, CerS6 was deleted in human hepatocytes and were incubated with EtOH and/or C16:0-ceramides. RNAseq analysis was performed in mice and in liver from patients with different stages of ALD and diseased controls. ResultsAfter six weeks on an EtOH diet, CerS6 KO mice had reduced body weight, food intake, and %fat mass compared to WT mice. Male (but not female) EtOH-fed KO mice showed significantly higher O2 consumption, CO2 production, respiratory exchange ratio, and energy expenditure (P<0.05 for all) during the dark period compared to EtOH-fed WT mice. In response to EtOH, WT mice developed mild hepatic steatosis, while steatosis was alleviated in KO mice as determined by H&E and ORO staining. KO mice showed significantly decreased long-chain ceramide species, especially C16:0 ceramides, in the serum and liver tissues compared to WT mice. CerS6 deletion decreased serum TG and NEFA only in male not female mice. CerS6 deletion improved glucose tolerance and insulin resistance in EtOH-fed mice of both sexes. RNAseq analysis revealed that 74 genes are significantly upregulated and 66 genes are downregulated by CerS6 deletion in EtOH-fed male mice, with key network pathways including TG biosynthetic process, positive regulation of lipid localization, and fat cell differentiation. Similar to RNAseq results, absence of CerS6 significantly decreased mRNA expression of lipid droplet associated proteins in EtOH-fed mice. In vitro, EtOH stimulation significantly increased PLIN2 protein expression in VL-17A cells while CerS6 deletion inhibited EtOH-mediated PLIN2 upregulation. C16:0-ceramide treatment significantly increased PLIN2 protein expression compared to CON. Importantly, progression of ALD in humans was associated with increased CerS6 hepatic expression. ConclusionsOur findings demonstrate that CerS6 deletion attenuates EtOH-induced weight gain and hepatic steatosis and improves glucose homeostasis in mice fed an EtOH diet. Notably, we unveil that CerS6 plays a major role as a regulator of lipid droplet biogenesis in alcoholic intra-hepatic lipid droplet formation. Together, our data suggest that CerS6 may be targeted for treatment for early stage ALD.

pathology↗

bioRxiv2022

Variant to function mapping at single-cell resolution through network propagation

With burgeoning human disease genetic associations and single-cell genomic atlases covering a range of tissues, there are unprecedented opportunities to systematically gain insights into the mechanisms of disease-causal variation. However, sparsity and noise, particularly in the context of single-cell epigenomic data, hamper the identification of disease- or trait-relevant cell types, states, and trajectories. To overcome these challenges, we have developed the SCAVENGE method, which maps causal variants to their relevant cellular context at single-cell resolution by employing the strategy of network propagation. We demonstrate how SCAVENGE can help identify key biological mechanisms underlying human genetic variation including enrichment of blood traits at distinct stages of human hematopoiesis, defining monocyte subsets that increase the risk for severe coronavirus disease 2019 (COVID-19), and identifying intermediate lymphocyte developmental states that are critical for predisposition to acute leukemia. Our approach not only provides a framework for enabling variant-to-function insights at single-cell resolution, but also suggests a more general strategy for maximizing the inferences that can be made using single-cell genomic data.

genomics↗

bioRxiv2021

Diverse northern Asian and Jomon-related genetic structure discovered among socially complex Three Kingdoms period Gaya region Koreans

The genetic history of prehistoric and protohistoric Korean populations is not well understood due to the lack of ancient Korean genomes. Here, we report the first paleogenomic data from Korea; eight shotgun-sequenced genomes (0.7x[~]6.1x coverage) from two archeological sites in Gimhae: Yuha-ri shell mound and Daesung-dong tumuli, the most important funerary complex of the Gaya confederacy. All eight individuals are from the Korean Three Kingdoms period (4th-7th century CE), during which there is archaeological evidence of extensive trade connections with both northern (modern-day China) and eastern (modern-day Japan) kingdoms. All genomes are best modeled as an admixture between a northern-Chinese Iron Age genetic source and a Japanese-Jomon-related ancestry. The proportion of Jomon-related ancestry suggests the presence of two genetic groups within the population. The observed substructure indicates diversity among the Gaya population that is not related to either social status or sex. Teaser1,700-year-old genomes reveal the genetic diversity of ancient Koreans in the Gimhae region.

evolutionary biology↗

bioRxiv2021

Genome assembly of the tayra (Eira barbara, Mustelidae) and comparative genomic analysis reveal adaptive genetic variation in the subfamily Guloninae

Species of the mustelid subfamily Guloninae inhabit diverse habitats on multiple continents, and occupy a variety of ecological niches. They differ in feeding ecologies, reproductive strategies and morphological adaptations. To identify candidate loci associated with adaptations to their respective environments, we generated a de novo assembly of the tayra (Eira barbara), the earliest diverging species in the subfamily, and compared this with the genomes available for the wolverine (Gulo gulo) and the sable (Martes zibellina). Our comparative genomic analyses included searching for signs of positive selection, examining changes in gene family sizes, as well as searching for species-specific structural variants (SVs). Among candidate loci associated with phenotypic traits, we observed many related to diet, body condition and reproduction. For example, for the tayra, which has an atypical gulonine reproductive strategy of aseasonal breeding, we observe species-specific changes in many pregnancy-related genes. For the wolverine, a circumpolar hypercarnivore that must cope with seasonal food scarcity, we observed many changes in genes associated with diet and body condition. All types of genomic variation examined contributed substantially to the identification of candidate loci. This strongly argues for consideration of variation other than single nucleotide polymorphisms in comparative genomics studies aiming to identify loci of adaptive significance.

evolutionary biology↗

bioRxiv2021

Individualized prediction of future cognition using baseline developmental changes in cortical anatomy

Predictive modeling studies have started to reveal brain measures underlying cognition; however, most studies are based on cross-sectional data (static final brain measures acquired at one time point). Since brain development comprises of continuously ongoing events leading to cognitive development, predictive modeling studies need to consider dynamic as opposed to static final brain measures. Using longitudinal neuroimaging and cognitive data (global executive composite score, an index of executive function) from 82 individuals (aged 5-14 years, scanned 3 times), we built highly accurate prediction models (r=0.61, p=1.6e-09) of future cognition (assessed at visit 3) based on baseline developmental changes in cortical anatomy (from visit 1 to 2). More importantly, dynamic brain measures (change in cortical anatomy from visit 1 to 2) and not static brain measures (cortical anatomy at visit 1 and 2) were critical for predicting future cognition, suggesting the need for considering dynamic brain measures in predicting cognitive outcomes.

neuroscience↗

bioRxiv2021

The Lithuanian reference genome LT1 - a human de novo genome assembly with short and long read sequence and Hi-C data

We present LT1, the first high-quality human reference genome from the Baltic States. LT1 is a female de novo human reference genome assembly constructed using 57x of ultra-long nanopore reads and 47x of short paired-end reads. We also utilized 72 Gb of Hi-C chromosomal mapping data to maximize the assemblys contiguity and accuracy. LT1s contig assembly was 2.73 Gbp in length comprising of 4,490 contigs with an N50 value of 13.4 Mbp. After scaffolding with Hi-C data and extensive manual curation, we produced a chromosome-scale assembly with an N50 value of 138 Mbp and 4,699 scaffolds. Our gene prediction quality assessment using BUSCO identify 89.3% of the single-copy orthologous genes included in the benchmarking set. Detailed characterization of LT1 suggested it has 73,744 predicted transcripts, 4.2 million autosomal SNPs, 974,000 short indels, and 12,330 large structural variants. These data are shared as a public resource without any restrictions and can be used as a benchmark for further in-depth genomic analyses of the Baltic populations.

genomics↗

bioRxiv2021

Robust T1 MRI cortical surface pipeline for neonatal brain and systematic evaluation using multi-site MRI datasets

The human brain grows the most dramatically during the perinatal and early postnatal periods, during which preterm birth or perinatal injury that may alter brain structure and lead to developmental anomalies. Thus, characterizing cortical thickness of developing brains remains an important goal. However, this task is often complicated by inaccurate cortical surface extraction due to small-size brains. Here, we propose a novel complex framework for the reconstruction of neonatal WM and pial surfaces, accounting for large partial volumes due to small-size brains. The proposed approach relies only on T1-weighted images unlike previous T2-weighted image-based approaches while only T1-weighted images are sometimes available under the different clinical/research setting. Deep neural networks are first introduced to the neonatal MRI pipeline to address the mis-segmentation of brain tissues. Furthermore, this pipeline enhances cortical boundary delineation using combined models of the CSF/GM boundary detection with edge gradient information and a new skeletonization of sulcal folding where no CSF voxels are seen due to the limited resolution. We also proposed a systematic evaluation using three independent datasets comprising 736 preterm and 97 term neonates. Qualitative assessment for reconstructed cortical surfaces shows that 86.9% are rated as accurate across the three site datasets. In addition, our landmark-based evaluation shows that the mean displacement of the cortical surfaces from the true boundaries was less than a voxel size (0.532{+/-}0.035mm). Evaluating the proposed pipeline (namely NEOCIVET 2.0) shows the robustness and reproducibility across different sites and different age-groups. The mean cortical thickness measured positively correlated with postmenstrual age (PMA) at scan (p<0.0001); Cingulate cortical areas grew the most rapidly whereas the inferior temporal cortex grew the least rapidly. The range of the cortical thickness measured was biologically congruent (1.3mm at 28 weeks of PMA to 1.8mm at term equivalent). Cortical thickness measured on T1 MRI using NEOCIVET 2.0 was compared with that on T2 using the established dHCP pipeline. It was difficult to conclude that either T1 or T2 imaging is more ideal to construct cortical surfaces. NEOCIVET 2.0 has been open to the public through CBRAIN (https://mcin-cnim.ca/technology/cbrain/), a web-based platform for processing brain imaging data.

bioinformatics↗

bioRxiv2021

Mutational impact and signature of ionizing radiation

Whole-genome sequencing (WGS) of human tumors and normal cells exposed to various carcinogens has revealed distinct mutational patterns that provide deep insights into the DNA damage and repair processes. Although ionizing radiation (IR) is conventionally known as a strong carcinogen, its genome-wide mutational impacts have not been comprehensively investigated at the single-nucleotide level. Here, we explored the mutational landscape of normal single-cells after exposure to the various levels of IR. On average, 1 Gy of IR exposure generated [~]16 mutational events with a spectrum consisting of predominantly small nucleotide deletions and a few characteristic structural variations. In [~]30% of the post-irradiated cells, complex genomic rearrangements, such as chromoplexy, chromothripsis, and breakage-fusion-bridge cycles, were resulted, indicating the stochastic and chaotic nature of DNA repair in the presence of the massive number of concurrent DNA double-strand breaks. These mutational signatures were confirmed in the genomes of 22 IR-induced secondary malignancies. With high-resolution genomic snapshots of irradiated cells, our findings provide deep insights into how IR-induced DNA damage and subsequent repair processes operate in mammalian cells.

genomics↗

bioRxiv2020

Platycodin D prevents both lysosome- and TMPRSS2-driven SARS-CoV-2 infection in vitro by hindering membrane fusion

An ongoing pandemic of coronavirus disease 2019 (COVID-19) is now the greatest threat to the global public health. Herbal medicines and their derived natural products have drawn much attention to treat COVID-19, but there has been no natural product showing inhibitory activity against SARS-CoV-2 infection with detailed mechanism. Here, we show that platycodin D (PD), a triterpenoid saponin abundant in Platycodon grandiflorum (PG), a dietary and medicinal herb commonly used in East Asia, effectively blocks the two main SARS-CoV-2 infection-routes via lysosome- and transmembrane protease, serine 2 (TMPRSS2)-driven entry. Mechanistically, PD prevents host-entry of SARS-CoV-2 by redistributing membrane cholesterol to prevent membrane fusion, which can be reinstated by treatment with a PD-encapsulating agent. Furthermore, the inhibitory effects of PD are recapitulated by a pharmacological inhibition or gene-silencing of NPC1, which is mutated in Niemann-Pick type C (NPC) patients displaying disrupted membrane cholesterol. Finally, readily available local foods or herbal medicines containing PG root show the similar inhibitory effects against SARS-CoV-2 infection. Our study proposes that PD is a potent natural product for preventing or treating COVID-19 and that a brief disruption of membrane cholesterol can be a novel therapeutic approach against SARS-CoV-2 infection.

pharmacology and toxicology↗