Biology subjects

Kim, W. J.

Publications and source records attributed to Kim, W. J..

32 records · Page 2Linked to original sources

bioRxiv2024

All-trans retinoic acid induces durable tumor immunity in IDH-mutant gliomas by rescuing transcriptional repression of the CRBP1-retinoic acid axis

Diffuse gliomas are epigenetically dysregulated, immunologically cold, and fatal tumors characterized by mutations in isocitrate dehydrogenase (IDH). Although IDH mutations yield a uniquely immunosuppressive tumor microenvironment, the regulatory mechanisms that drive the immune landscape of IDH mutant (IDHm) gliomas remain unknown. Here, we reveal that transcriptional repression of retinoic acid (RA) pathway signaling impairs both innate and adaptive immune surveillance in IDHm glioma through epigenetic silencing of retinol binding protein 1 (RBP1) and induces a profound anti-inflammatory landscape marked by loss of inflammatory cell states and infiltration of suppressive myeloid phenotypes. Restorative retinoic acid therapy in murine glioma models promotes clonal CD4+ T cell expansion and induces tumor regression in IDHm, but not IDH wildtype (IDHwt), gliomas. Our findings provide a mechanistic rationale for RA immunotherapy in IDHm glioma and is the basis for an ongoing investigator-initiated, single-center clinical trial investigating all-trans retinoic acid (ATRA) in recurrent IDHm human subjects.

cancer biology↗

bioRxiv2022

Immature Myeloid Cell Deposition in Old Bone Marrow Revealed by Single-Cell Transcriptome Analysis

Aging causes dysfunction of innate immunity, although hematopoietic stem cells of aged bone marrow (BM) show an increased differentiation potential to myeloid lineage cells. The alteration of cellular heterogeneity and intercellular communications between BM immune cells may provide important clues to understanding age-dependent immune dysfunction. Here, we provide a deep single-cell transcriptomic analysis of total immune cell populations of young and old BM. We identified the well-organized differentiation status of 11 myeloid/lymphoid lineage cell populations and age-dependent alterations in the proportions of cells. The neutrophil lineages showed the most prominent alteration by aging, and subclustering of neutrophils indicated that the specific immature neutrophils are increased in old BM. In addition, we identified age-dependent alterations in secretory phenotypes associated with a decline in innate immunity and immune cell differentiation. Among these secretory phenotypes, SPP1 could be suggested as a representative signal that triggers myeloid skewing and immature neutrophil deposition in aged BM. Collectively, these results provide a novel link between the altered immune cell proportions in BM and age-dependent dysregulation of innate immunity.

bioinformatics↗

bioRxiv2022

Surface glia predominantly contribute to the development of ALS/FTD in Drosophila model

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder characterized by motor neuron degeneration in the primary motor neurons. C9orf72 repeat expansion mutation is the most prevalent genetic causes of ALS/FTD. Due to the complexity of ALS, there has been no successful therapy for the condition. The traditional neurocentric concept of ALS derives in part from the assumption that the degradation of motor neuron (MN) cells in ALS is driven by cell-autonomous mechanisms, however, recent research has focused on the non-cell-autonomous pathogenic mechanisms such as glial, immune cells and blood-brain barriers participate in the degeneration of MNs in ALS. Drosophila melanogaster is widely used as a genetic model for ALS, giving essential mechanistic data on disease onset and development. Using newly developed genetic tools to individually mark each subtype of the adult glial system in the fruit fly, we demonstrate that surface glia are the major glial subtypes for the pathogenesis of C9orf72-mediated ALS/FTD.

pathology↗

bioRxiv2022

Glia-specific expression of neuropeptide receptor Lgr4 regulates development and adult physiology in Drosophila

Similar to the human brain, Drosophila glia may well be divided into several subtypes that each carry out specific functions. Glial GPCRs plays key roles in crosstalk between neurons and glia. Drosophila Lgr4 (dLgr4) is a human relaxin receptor homolog involved in angiogenesis, cardiovascular regulation, collagen remodeling, and wound healing. Recent study suggests that ilp7 might be the ligand for Lgr4 and regulates escape behavior of Drosophila larvae. Here we demonstrate that Drosophila Lgr4 expression in glial cells, not neurons, is necessary for early development, adult behavior, and lifespan. Reducing the Lgr4 level in glial cells, but not neurons, disrupts Drosophila development, although knocking down other LGR family members in glia has no impact. Adult-specific knockdown of Lgr4 in glia but not neurons reduce locomotion, male reproductive success, and animal longevity. The investigation of how glial expression of Lgr4 contributes to this behavioral alteration will increase our understanding of how insulin signaling via glia selectively modulates neuronal activity and behavior.

genetics↗

bioRxiv2022

Multisensory inputs control the regulation of time investment for mating by sexual experience in male Drosophila melanogaster

Males have finite resources to spend on reproduction. Thus, males rely on a time investment strategy to maximize their reproductive success. For example, male Drosophila melanogaster extends their mating duration when surrounded by conditions enriched with rivals. Here we report a novel form of behavioral plasticity whereby male fruit flies exhibit a shortened duration of mating when they are sexually experienced; we refer to this plasticity as shorter-mating-duration (SMD). SMD is a plastic behavior and requires sexually dimorphic taste neurons. We identified several neurons in the male foreleg and midleg that express specific sugar, pheromone and mechanosensory receptors. Using a cost-benefit model and behavioral experiments, we further show that SMD behavior exhibits adaptive behavioral plasticity in male flies. Thus, our study delineates the molecular and cellular basis of the sensory inputs required for SMD; this represents a plastic interval timing behavior that could serve as a model system to study how multisensory inputs converge to modify interval timing behavior for improved adaptation. ONE SENTENCE SUMMARYMale flies use information derived from their previous sexual experiences from multiple sensory inputs to optimize their investment in mating.

neuroscience↗

bioRxiv2022

Gut microbiota analysis of the western honeybee (Apis mellifera L.) infested with the mite Varroa destructor reveals altered bacterial and archaeal community

The western honeybee, Apis mellifera L., is a crop pollinator that makes royal jelly and other hive products. However, widespread concerns arise about opportunistic diseases (e.g., bacteria, fungi, or mites) or chemicals that have an effect on the health and number of colonies, as well as their activity. The relationships between the gut microbiota and its host are currently being researched extensively. The effects of Varroa destructor infection on the gut microbial community, in particular, have received little investigation. This work utilized amplicon sequencing of the bacterial and archaeal 16S rRNA genes to assess the bacterial and archaeal communities of adult bee groups (healthy and affected by Varroa designed in NG and VG, respectively) and larvae from Varroa destructor-infected hives. Our results suggest that the genus Bombella was substantially dominant in larvae, while the genera Gillamella, unidentified Lactobacillaceae, and Snodgrassella were significantly dominant in adult bees. NG and VG, on the other hand, did not differ statistically significantly. The PICRUSt study revealed a significant difference in the KEGG classifications of larvae and adult bee groups. A greater number of genes involved in cofactor and vitamin production were identified in larvae. Additionally, despite the complexity of the honeybees bacterial community, all groups exhibited a straightforward archaeal community structure. Surprisingly, methanogen was detected in low abundance in the microbiota of honeybees. In summary, larvae and adult bees infected with Varroa destructor exhibit altered gut microbiota composition and function.

microbiology↗

bioRxiv2022

Targeting TRIP13 in Wilms Tumor with Nuclear Export Inhibitors

Wilms tumor (WT) is the most common renal malignancy of childhood. Despite improvements in the overall survival, relapse occurs in ~15% of patients with favorable histology WT (FHWT). Half of these patients will succumb to their disease. Identifying novel targeted therapies in a systematic manner remains challenging in part due to the lack of faithful preclinical in vitro models. We established ten short-term patient-derived WT cell lines and characterized these models using low-coverage whole genome sequencing, whole exome sequencing and RNA-sequencing, which demonstrated that these ex-vivo models faithfully recapitulate WT biology. We then performed targeted RNAi and CRISPR-Cas9 loss-of-function screens and identified the nuclear export genes (XPO1 and KPNB1) as strong vulnerabilities. We observed that these models are sensitive to nuclear export inhibition using the FDA approved therapeutic agent, selinexor (KPT-330). Selinexor treatment of FHWT suppressed TRIP13 expression, which was required for survival. We further identified in vitro and in vivo synergy between selinexor and doxorubicin, a chemotherapy used in high risk FHWT. Taken together, we identified XPO1 inhibition with selinexor as a potential therapeutic option to treat FHWTs and in combination with doxorubicin, leads to durable remissions in vivo.

cancer biology↗

bioRxiv2019

Astrocyte-like glia-specific gene deathstar is crucial for normal development, adult locomotion and lifespan of male Drosophila

The brain of Drosophila melanogaster is a complex organ with various cell types, orchestrating the physiology and behaviors of the fly. While each cell type in the Drosophila brain is known to express a unique set of genes, their complete genetic profile is still unknown. Advances in the RNA-sequencing techniques at single cell resolution facilitate identifying novel cell type-specific markers and/or examining the specificity of the available markers. In this study, exploiting a single cell RNA sequencing data of Drosophila optic lobe (which comprises two thirds of the brain with extensive cell type diversity), we first categorized cell types based on their known molecular markers, then the genes with enriched expression in astrocytes were identified. Consistent with previous findings, the known glial markers CG34335, Inx2 and nrv2 as well as the astrocytic genes CG9394, Eaat1, Gat, Gs2 and CG1552 exhibited enriched expression in the identified astrocyte cluster. Moreover, we identified CG11000 as a gene with positive expression correlation with the astrocytic marker Eaat1. The positive expression correlation between CG11000 and Eaat1 genes was also observed in the single-cell RNA-sequencing data of Drosophila mid-brain as well as in the bulk RNA-sequencing data of Drosophila whole brain during development. Immunostaining of the brains dissected from adult flies showed overlapping fluorescence signals of CG11000 and Eaat1 expression, supporting co-expression of these genes in a set of single cells in Drosophila optic lobe. At the physiological level, RNAi-mediated suppression of CG11000 impeded th normal development of male flies without any effects on females. In adult flies, CG11000 suppression affected the locomotion activity and lifespan of D. melanogaster in an astrocyte-specific manner, suggesting pivotal role of CG11000 gene in astrocytes.

genetics↗

bioRxiv2019

Neuropeptide relay between SIFa signaling controls the experience-dependent mating duration of male Drosophila

Drosophila melanogaster is a suitable model for investigating how neuropeptides influence animal behaviours and physiology. We previously reported that two behavioural paradigms control mating duration of male Drosophila, called Longer-Mating-Duration (LMD) and Shorter-Mating-Duration (SMD) that are induced through socio-sexual environment prior to copulation. Understanding the molecular and cellular mechanisms by which males exhibit plasticity to different social cues remains poorly understood. Here, we show that SIFa modulates the neural circuitry for both LMD and SMD. Neuropeptide-to-neuropeptide communication, so called neuropeptide relay plays a key role to mediate this control. We identified that 7 neuropeptides expressed in SIFa Receptor-positive cells are functionally important to regulate either LMD and/or SMD. The modulation of two independent mating duration behaviour by the different SIFa-mediated neuropeptide relay will help to further investigate how the neuropeptidergic modulation can control complex behaviours.

animal behavior and cognition↗

bioRxiv2018

Renal medullary carcinomas depend upon SMARCB1 loss and are sensitive to proteasome inhibition

Renal medullary carcinoma (RMC) is a rare and deadly kidney cancer in patients of African descent with sickle cell trait. Through direct-to-patient outreach, we developed genomically faithful patient-derived models of RMC. Using whole genome sequencing, we identified intronic fusion events in one SMARCB1 allele with concurrent loss of the other allele, confirming that SMARCB1 loss occurs in RMC. Biochemical and functional characterization of these RMC models revealed that RMC depends on the loss of SMARCB1 for survival and functionally resemble other cancers that harbor loss of SMARCB1, such as malignant rhabdoid tumors or atypical teratoid rhabdoid tumors. We performed RNAi and CRISPR-Cas9 loss of function genetic screens and a small-molecule screen and identified UBE2C as an essential gene in SMARCB1 deficient cancers. We found that the ubiquitin-proteasome pathway was essential for the survival of SMARCB1 deficient cancers in vitro and in vivo. Genetic or pharmacologic inhibition of this pathway leads to G2/M arrest due to constitutive accumulation of cyclin B1. These observations identify a synthetic lethal relationship that may serve as a therapeutic approach for patients with SMARCB1 deficient cancers.

cancer biology↗

bioRxiv2018

Comprehensive genetic analysis by whole exome sequencing in 352 Korean pediatric patients with unknown neurodevelopmental disorders

ImportanceAccurate diagnosis of pediatric patients with complicated neurological problems demands a well-coordinated combination of robust genetic analytic capability and delicate clinical evaluation. It should be tested whether this challenge can be augmented by whole exome sequencing (WES).\n\nObjectiveTo evaluate the utility of WES-based diagnosis and discovery of novel variants of undiagnosed patients with complex neurodevelopmental problems in a country with a centralized medical system.\n\nDesign, setting, and participantsA cohort of 352 Korean patients, believed to cover a major portion of the entire country from July 2014 to April 2017, with a broad spectrum of neurodevelopmental disorders without any pathogenic variants revealed by conventional methods were evaluated by trio-based WES at Seoul National University Childrens Hospital.\n\nExposuresWES of patients and parents and subsequent evaluation of genetic variants.\n\nMain outcomes and measuresGenetic variants from each patient were evaluated for known disease association and novel variants were assessed for possible involvement with neurodevelopment process.\n\nResultsWe identified disease-causing variants, including newly discovered variants, in 57.4% of the probands, who had underwent a mean of 5.6 years of undiagnosed periods and visited mean of 2.3 tertiary hospitals. The cohort included 112 patients with variants that were previously reported as pathogenic (31.8%), 16 patients with copy number variants (4.5%) and 27 patients with variants that were associated with different clinical symptoms (7.7%). We also discovered potentially pathogenic variants from 47 patients that required further functional assessments (13.4%) and demonstrated potential implications in neurodevelopmental disorders. Following the genetic analysis, we provided more precise treatments to selected patients. A few clinical vignettes are presented that illuminate the potential diagnostic pitfalls that one could have encountered without this approach.\n\nConclusions and relevanceOur results highlight the utility of WES-based diagnosis for improved patient care in a country with a centralized medical system and discovery of novel pathophysiology mechanisms.\n\nKey pointsO_ST_ABSQuestionC_ST_ABSWhat is the advantage of whole exome sequencing based diagnosis of pediatric neurology patients with unknown rare symptoms in a large tertiary clinic in a country with a centralized medical system?\n\nFindingsWhole exome sequencing of 352 Korean patients, with a mean of 5.7 years of undiagnosed period, yielded 44.0% of conservative diagnostic yield. A number of cases were directly benefitted by trio-based WES via termination of diagnostic odyssey, genetic counseling for next offspring, or suggestion of more effective and customized treatment options.\n\nMeaningWe report on the establishment of a national-level whole exome-based diagnosis system, with emphasis on deliberate integration of clinical interpretation and genetic analysis. Whole exome sequencing should be a choice of diagnostic tools for pediatric neurologic patients with ambiguous symptoms.

genetics↗

bioRxiv2018

Expanded genetic landscape of chronic obstructive pulmonary disease reveals heterogeneous cell type and phenotype associations

Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide novel insights into disease pathogenesis. To broaden COPD genetic risk loci discovery and identify cell type and phenotype associations we performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci with P value < 5x10-8; 47 were previously described in association with either COPD or population-based lung function. Of the remaining 35 novel loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified enrichment for loci in lung tissue, smooth muscle and alveolar type II cells. We found 9 shared genomic regions between COPD and asthma and 5 between COPD and pulmonary fibrosis. COPD genetic risk loci clustered into groups of quantitative imaging features and comorbidity associations. Our analyses provide further support to the genetic susceptibility and heterogeneity of COPD.

genetics↗

bioRxiv2017

Computational docking reveals evolutionary conservation of a specific interaction between 15d-Prostaglandin-J2 and eIF4A.

15-deoxy-delta 12,14-prostaglandin J2 (15d-PGJ2) is anti-inflammatory/antineoplastic prostaglandin which functions through covalent binding to cysteine residues of various target proteins. We previously showed that 15d-PGJ2 mediated anti-inflammatory responses are dependent on the translational inhibition through its interaction with eIF4A. Binding of 15d-PGJ2 to eIF4A specifically blocks the interaction between eIF4G and eIF4A leads to the formation of stress granules (SGs), which cluster mRNAs with inhibited translation. Here we show that the binding between 15d-PGJ2 and eIF4A specifically blocks the interaction between the MIF4G domain of eIF4G and eIF4A. To reveal the mechanism of this interaction, we used computational simulation-based docking studies and identified that the carboxyl tail of 15d-PGJ2 could stabilize the binding of 15d-PGJ2 to eIF4A through arginine 295 of eIF4A, which is the first suggestion that the 15d-PGJ2 tail play a physiological role. Interestingly, the putative 15d-PGJ2 binding site on eiF4A is conserved across many species, suggesting a biological role. Our data propose that studying 15d-PGJ2 and its targets will may uncover new therapeutic approaches in anti-inflammatory drug discovery.

molecular biology↗

bioRxiv2016

Sexually satiated male Drosophila melanogaster uses gustatory-to-neuropeptide integrative circuits to reduce time investment for mating

Males rely on a time investment strategy to maximize reproductive success. Here we report a novel behavioral plasticity whereby male fruit flies exhibit a shortened mating duration when sexually satiated, which we named Shorter-Mating-Duration (SMD). SMD requires the sexually dimorphic Gr5a-positive neurons for detecting female body pheromones. The memory circuitry within the ellipsoid body (EB) and mushroom body (MB) brain regions is crucial for SMD, which depends on the circadian clock genes Clock and cycle, but not timeless or period. SMD also relies on signaling via the neuropeptide sNPF, but not PDF or NPF. Sexual experience modifies the neuronal activity of a subset of sNPF-positive neurons involved in neuropeptide signaling, which modulates SMD. Thus, our study delineates the molecular and cellular basis for SMD - a plastic social behavior that serves as a model system to study how the brain switches the internal states between sexual drive and satiety.

neuroscience↗