Biology subjects

Lee, J.-H.

Publications and source records attributed to Lee, J.-H..

105 records · Page 6Linked to original sources

bioRxiv2019

Dual activity of PNGM-1, a metallo-β-lactamase and tRNase Z, pinpoints the evolutionary origin of subclass B3 metallo-β-lactamases

Antibiotic resistance is a steadily increasing global problem which could lead to a fundamental upheaval in clinical care with the potential to return us to the pre-antibiotic era1-4. The production of {beta}-lactamases, a group of enzymes that confer antibiotic resistance in Gram-negative bacteria, is now one of the major barriers in treating Gram-negative infections5. {beta}-Lactamases are classified according to their catalytic mechanisms into serine {beta}-lactamases and metallo-{beta}-lactamases6,7. There are functional and structural similarities between serine {beta}-lactamases and penicillin-binding proteins, and so serine {beta}-lactamases are thought to have evolved from a penicillin-binding protein7,8. Given the functional and structural differences between serine {beta}-lactamases and metallo-{beta}-lactamases, metallo-{beta}-lactamases are thought to have evolved from a protein other than a penicillin-binding protein, but to date this ancestor remains unknown8-11. We discovered PNGM-1, the first subclass B3 metallo-{beta}-lactamase, in deep-sea sediments that predate the antibiotic era12. Here we discover the dual activity of PNGM-1, pinpointing the evolutionary origin of subclass B3 metallo-{beta}-lactamases. Phylogenetic analysis suggested that PNGM-1 could yield insights into the evolutionary origin of subclass B3 metallo-{beta}-lactamases. We reveal the structural similarities between tRNase Zs and PNGM-1, which prompted us to investigate their evolutionary relationship and the possibility of them possessing dual enzymatic activities. We demonstrate that PNGM-1 has dual activity with both true metallo-{beta}-lactamase and tRNase Z activity, suggesting that PNGM-1 is thought to have evolved from a tRNase Z. We also show kinetic and structural comparisons between PNGM-1 and other proteins including subclass B3 metallo-{beta}-lactamases and tRNase Zs. These comparisons revealed that the B3 metallo-{beta}-lactamase activity of PNGM-1 is a promiscuous activity and subclass B3 metallo-{beta}-lactamases are thought to have evolved through PNGM-1 activity. Our work provides a foundation for the evolution of tRNase Z into subclass B3 metallo-{beta}-lactamases through the dual activity of PNGM-1.

microbiology↗

bioRxiv2019

Predicting potential current distribution of Lycorma delicatula (Hemiptera: Fulgoridae) using MaxEnt model in South Korea

Lycorma delicatula (Hemiptera: Fulgoridae) is invasive insect in Korea which causes plant damages by sucking and sooty molds. Lycorma delicatula was first detected in South Korea in 2004, where its introduction and spreading possibly were affected by human activity-related factors. Here, we used MaxEnt to describe current distribution of L. delicatula in Korea and tried to find out the impact of human influences for distribution. We used 143 sites of occurrence data, 19 bioclimatic variables, duration of temperature below -11{degrees}C, average daily minimum temperature in January, cumulative thermal unit variable, the distribution of grape orchard variable and human footprint to create models. These models were estimated by two sets of 24 candidates with feature combinations and regularization multipliers. In addition, these two sets were created as models with and without footprint for how human influence affect to distribution. Model selection for optimal model was performed by selecting a model with a lowest sum of each rank in small sample-size corrected Akaikes information criterion and difference between training and test AUC. Model of LQ10 parameter combinations was selected as optimal models for both model sets. Consequently, both of distribution maps from these models showed similar patterns of presence probability for L. delicatula. Both models expected that low altitude regions were relatively more suitable than mountain areas in Korea. Footprint might be limited for the distribution and L. delicatula might already occupy most of available habitats. Human-related factors might contribute to spread of L. delicatula to uninfected areas.

ecology↗

bioRxiv2019

Cell wall integrity signaling regulates cell wall regeneration via transcriptional activation in Chlamydomonas reinhardtii

An intact cell wall is critical for protecting the cell from osmotic challenges and harmful environments. Signaling mechanisms are necessary to monitor cell wall integrity and to regulate cell wall production and remodeling during growth and division cycles. The green alga, Chlamydomonas, has a proteinaceous cell wall of defined structure that is readily removed by gametolysin (g-lysin), a metalloprotease released during sexual mating. Naked cells treated with g-lysin induce the mRNA accumulation of > 100 cell wall-related genes within an hour, offering a system to study signaling and regulatory mechanisms for de novo cell wall assembly. Combining quantitative RT-PCR and luciferase reporter assays to probe transcript accumulation and promoter activity, we revealed that up to 500-fold upregulation of cell wall-related genes was driven at least partly by transcriptional activation upon g-lysin treatment. To investigate how naked cells trigger this rapid transcriptional activation, we tested whether osmotic stress and cell wall integrity are involved in this process. Under a constant hypotonic condition, comparable levels of cell wall-gene activation were observed by g-lysin treatment. In contrast, cells in an iso- or hypertonic condition showed up to 80% reduction in the g-lysin-induced gene activation, suggesting that hypotonic conditions are required for full-scale responses to g-lysin treatment. To test whether mechanical perturbation is involved, we isolated and examined a new set of cell wall mutants with defective or little cell walls. All cell wall mutants examined showed a constitutive upregulation of cell wall-related genes at the level, which would only be achieved by the g-lysin treatment in wild-type cells. Our study suggests a signaling that monitors mechanical defects of cell walls and regulates cell wall-gene expression in Chlamydomonas, which may relate to cell wall integrity signaling mechanisms in plants.

plant biology↗

bioRxiv2018

Ezh2-dependent epigenetic reprogramming controls a developmental switch between modes of gastric neuromuscular regulation

Physiological interconversion between specialized cell types has only been described in a few mammalian tissues and the mechanisms remain obscure. Using genetic lineage tracing during postnatal development and in-vitro models we demonstrate conversion of gastric interstitial cells of Cajal (ICC), regulatory cells that electrically pace phasic contractions and mediate nitrergic and cholinergic neural control of smooth muscle cells, into phenotypically distinct \"fibroblast-like\" interstitial cells (FLC), which only mediate purinergic signaling. Mechanistically, we find this transition to be epigenetically governed by H3K27 trimethylation of cell identity-related promoters whose susceptibility to repression is predicted by H3K27 acetylation patterns in ICC. The phenotypic switch was reversible by inhibition, knockdown or in-vivo genomic inactivation of the polycomb H3K27 methyl-transferase Ezh2. These results demonstrate a role for Ezh2-mediated epigenetic repression in physiological mammalian transdifferentiation and identify FLC as a reserve from which ICC can potentially be restored in common gastrointestinal disorders where ICC are depleted.\n\nGRAPHICAL ABSTRACT\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=157 SRC=\"FIGDIR/small/486423v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (38K):\norg.highwire.dtl.DTLVardef@e12f42org.highwire.dtl.DTLVardef@1e5c7beorg.highwire.dtl.DTLVardef@9cbc21org.highwire.dtl.DTLVardef@34f28_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIGastric pacemaker cells (ICC) transdifferentiate into quiescent cells (FLC) in vivo\nC_LIO_LIICC-to-FLC shift switches neural control from nitrergic/cholinergic to purinergic\nC_LIO_LIEzh2-mediated H3K27me3 represses cell-identity genes during ICC-to-FLC transition\nC_LIO_LIEzh2 inhibition restores ICC numbers, phenotype and function\nC_LI\n\neTOC BLURBSyed et al. find aging to cause transdifferentiation of gastric pacemaker cells (interstitial cells of Cajal, ICC), which also communicate cholinergic and nitrergic neurotransmission to smooth muscle cells, into quiescent \"fibroblast-like cells\" (FLC), which only mediate purinergic signals. This switch is governed by Ezh2, whose inhibition can reverse ICC depletion.

molecular biology↗

bioRxiv2018

The draft genome of an octocoral, Dendronephthya gigantea

BackgroundCoral reefs composed of stony corals are threatened by global marine environmental changes. However, soft coral communities composed of octocorallian species, appear more resilient. The genomes of several species of cnidarians have been published, including stony corals, sea anemones, and hydra, but as of yet no octocoral species. To fill this phylogenetic gap within the cnidarian, we sequenced the octocoral, Dendronephthya gigantea, a non-symbiotic soft coral, commonly known as the carnation coral.\n\nFindingsThe D. gigantea genome size is approximately 276 Mb. A high-quality genome assembly was constructed using 29.85Gb (108x coverage) of PacBio long reads and 35.54Gb (128x coverage) of Illumina short paired-end reads resulting in the largest N50 value reported among cnidarian of 1.4 Mb. About 12 % of the genome consisted of repetitive elements. We found 28,879 protein-coding genes. This gene set contained about 94% metazoan single-copy orthologs, indicating the gene models were predicted with high quality compared to other cnidarians. Based on molecular phylogenetic analysis, octocoral and hexacoral divergence occurred approximately 544 million years ago. Moreover, there is a clear difference in Hox gene composition: unlike in hexacorals, Antp superclass member Evx gene was absent in D. gigantea.\n\nConclusionsWe present the first genome assembly of a non-symbiotic octocoral, D. gigantea to aid in the comparative genomic analysis of cnidarians, including comparisons of stony and soft corals and symbiotic and non-symbiotic corals. In addition, the genome of this species may provide clues about differential genetic coping mechanisms between soft and stony coral regarding the global warming.

genomics↗

bioRxiv2018

The jellyfish genome sheds light on the early evolution of active predation

BackgroundUnique among cnidarians, jellyfish have remarkable morphological and biochemical innovations that allow them to actively hunt in the water column. One of the first animals to become free-swimming, jellyfish employ pulsed jet propulsion and venomous tentacles to capture prey.\n\nResultsTo understand these key innovations, we sequenced the genome of the giant Nomuras jellyfish (Nemopilema nomurai), the transcriptomes of its bell and tentacles, and transcriptomes across tissues and developmental stages of the Sanderia malayensis jellyfish. Analyses of Nemopilema and other cnidarian genomes revealed adaptations associated with swimming, marked by codon bias in muscle contraction and expansion of neurotransmitter genes, along with expanded Myosin type II family and venom domains; possibly contributing to jellyfish mobility and active predation. We also identified gene family expansions of Wnt and posterior Hox genes, and discovered the important role of retinoic acid signaling in this ancient lineage of metazoans, which together may be related to the unique jellyfish body plan (medusa formation).\n\nConclusionsTaken together, the jellyfish genome and transcriptomes genetically confirm their unique morphological and physiological traits that have combined to make these animals one of the worlds earliest and most successful multi-cellular predators.

genomics↗

bioRxiv2018

Arginine culture turns on the elusive nitrogen starvation signal during robust phototrophic growth in Chlamydomonas

Under nitrogen (N) starvation, microalgae increase carbon storage in the form of lipid droplets while also downregulating photosynthesis and eventually terminating growth. To improve lipid yield, we asked whether lipid droplets and N starvation responses can be induced without limiting growth or photosynthesis. In the chlorophyte Chlamydomonas reinhardtii, gametogenesis is induced either by N starvation or by growth with arginine as the sole N source. We showed that arginine cultures supported robust phototrophic growth, constitutively turned on N starvation-induced genes, and increased lipid droplets. The lipids accumulated in arginine cultures exhibited strong enrichment of saturated and monounsaturated fatty acids, a preferred characteristic of biodiesel precursors. The diatom Phaeodactylum tricornutum also accumulated lipid droplets in arginine culture without growth impairment. We document a system wherein N starvation responses are induced without compromising photosynthesis or growth, thereby suited to the producing valuable chemicals and biofuel precursors without requiring stressors in microalgae.

plant biology↗

bioRxiv2018

Therapeutic effects of Hypoxia-Inducible Factor-1α (HIF-1α) on bone formation around implants in diabetic mice

Patients with uncontrolled diabetes are susceptible to implant failure due to impaired bone metabolism. Hypoxia-Inducible Factor 1 (HIF-1), a transcription factor that is up-regulated in response to reduced oxygen condition during the bone repair process after fracture or osteotomy, is known to mediate angiogenesis and osteogenesis. However, its function is inhibited under hyperglycemic conditions in diabetic patients. The aim of this study is to evaluate the effects of exogenous HIF-1 on bone formation around implants by applying HIF-1 to diabetic mice via a novel PTD-mediated DNA delivery system. Smooth surface implants (1mm in diameter; 2mm in length) were placed in the both femurs of diabetic and normal mice. HIF-1 and placebo gels were injected to implant sites of the right and left femurs, respectively: Normal mouse with HIF-1 gel (NH), Normal mouse with placebo gel (NP), Diabetic mouse with HIF-1 gel (DH), and Diabetic mouse with placebo gel (DP). RNA sequencing was performed 4 days after surgery. Based on RNA sequencing, Differentially Expressed Genes (DEGs) were identified and HIF-1 target genes were selected. Histologic and histomorphometric results were evaluated 2 weeks after the surgery. The results showed that bone-to-implant contact (BIC) and bone volume (BV) were significantly greater in the DH group than the DP group (p < 0.05). A total of 216 genes were differentially expressed in DH group compared to DP group. On the other hand, there were 95 DEGs in the case of normal mice. Twenty-one target genes of HIF-1 were identified in diabetic mice through bioinformatic analysis of DEGs. Among the target genes, NOS2, GPNMB, CCL2, CCL5, CXCL16 and TRIM63 were manually found to be associated with wound healing-related genes. In conclusion, local administration of HIF-1 via PTD may help bone formation around the implant and induce gene expression more favorable to bone formation in diabetic mice.

molecular biology↗

bioRxiv2018

Common ancestry of heterodimerizing TALE homeobox transcription factors across Metazoa and Archaeplastida

Homeobox transcription factors (TFs) in the TALE superclass are deeply embedded in the gene regulatory networks that orchestrate embryogenesis. Knotted-like homeobox (KNOX) TFs, homologous to animal MEIS, have been found to drive the haploid-to-diploid transition in both unicellular green algae and land plants via heterodimerization with other TALE superclass TFs, representing remarkable functional conservation of a developmental TF across lineages that diverged one billion years ago. To delineate the ancestry of TALE-TALE heterodimerization, we analyzed TALE endowment in the algal radiations of Archaeplastida, ancestral to land plants. Homeodomain phylogeny and bioinformatics analysis partitioned TALEs into two broad groups, KNOX and non-KNOX. Each group shares previously defined heterodimerization domains, plant KNOX-homology in the KNOX group and animal PBC-homology in the non-KNOX group, indicating their deep ancestry. Protein-protein interaction experiments showed that the TALEs in the two groups all participated in heterodimerization. These results indicate that the TF dyads consisting of KNOX/MEIS and PBC-containing TALEs must have evolved early in eukaryotic evolution, a likely function being to accurately execute the haploid-to-diploid transitions during sexual development.\n\nAuthor summaryComplex multicellularity requires elaborate developmental mechanisms, often based on the versatility of heterodimeric transcription factor (TF) interactions. Highly conserved TALE-superclass homeobox TF networks in major eukaryotic lineages suggest deep ancestry of developmental mechanisms. Our results support the hypothesis that in early eukaryotes, the TALE heterodimeric configuration provided transcription-on switches via dimerization-dependent subcellular localization, ensuring execution of the haploid-to-diploid transition only when the gamete fusion is correctly executed between appropriate partner gametes, a system that then diversified in the several lineages that engage in complex multicellular organization.

evolutionary biology↗

bioRxiv2018

Association between activities outside work and presenteeism among Korean wage workers : using nationwide survey

IntroductionPresenteeism is a significant global health issue nowadays and can influence to producitivity loss. So, there were many studies to analyse relationship between workplace factor and presenteeism. But a few studies have considered non-occupational factor. The purpose of this study was to examine the association between presenteeism and activities outside work, such as, volunteering, self-development, leisure/sports, gardening & house repair activity, in Korean wage workers.\n\nMethodsThis study analysed the 4th Korean Working Condition Survey(KWCS) and overall 19,294 wage workers participated. To find the relationship between presenteeism and activities outside work, multivariate logistic regression analysis was used after adjusting for general and occupational characteristics.\n\nResultsAmong self-development, leisure/sports and gardening & house repair activities significantly increased the odds ratio of presenteeism (Odds ratio[OR] =1.33, 95% confidence interval[CI]: 1.23-1.43, OR = 1.40, 95% CI: 1.29-1.51 and OR = 1.09, 95% CI: 1.01-1.18, respectively).\n\nConclusionsSome of activities outside work were related to presenteeism in Korean wage workers. Although many of previous studies addressed positive effect of those activities for health, this study showed negative effect of activities oudside work for health. And we should consider Korean organizational culture for this reason and need more structural studies to find out specific factors.

epidemiology↗

bioRxiv2018

Mapping molecular HLA typing data to UNOS antigen equivalents for improved virtual crossmatch

BackgroundVirtual crossmatch utilizes HLA typing and antibody screen assay data as a part of organ offers in deceased donor allocation systems. Histocompatibility labs must convert molecular HLA typings to antigen equivalencies for entry into the United Network for Organ Sharing (UNOS) UNet system. While an Organ Procurement and Transplantation Network (OPTN) policy document provides general guidelines for conversion, the process is complex because no antigen mapping table is available. We present a UNOS antigen equivalency table for all IMGT/HLA alleles at the A, B, C, DRB1, DRB3/4/5, DQA1, and DQB1 loci.\n\nMethodsAn automated script was developed to generate a UNOS antigen equivalency table. Data sources used in the conversion algorithm included the World Marrow Donor Association(WMDA) antigen table, the HLA Dictionary, and UNOS-provided tables. To validate antigen mappings, we converted National Marrow Donor Program (NMDP) high resolution allele frequencies to antigen equivalents and compared with the UNOS Calculated Panel Reactive Antibodies (CPRA) reference panel.\n\nResultsNormalized frequency similarity scores between independent NMDP and UNOS panels for 4 US population categories (Caucasian, Hispanic, African American and Asian/Pacific Islander) ranged from 0.85 to 0.97, indicating correct antigen mapping. An open source web application (ALLele to ANtigen (\"ALLAN\")) and web services were also developed to map unambiguous and ambiguous HLA typing data to UNOS antigen equivalents based on NMDP population-specific allele frequencies (http://www.transplanttoolbox.org).\n\nConclusionsThis tool sets a foundation for using molecular HLA typing to compute the virtual crossmatch and may aid in reducing typing discrepancies in UNet.

bioinformatics↗

bioRxiv2018

Building superfast muscles: insights from molecular parallelism in fast-twitch muscle proteins in echolocating mammals

Detecting associations between genomic changes and phenotypic differences is fundamental to understanding how phenotypes evolved. By systematically screening for parallel amino acid substitutions, we detected known as well as novel cases (Strc, Tecta, Cabp2) of parallelism between echolocating bats and toothed whales in proteins that could contribute to high frequency hearing adaptations. Interestingly, our screen also showed that echolocating mammals exhibit an unusually high number of parallel substitutions in fast-twitch muscle fiber proteins. Both bats and dolphins produce an extremely rapid call rate when homing in on their prey, which was shown in bats to be powered by specialized superfast muscles. We show that these genes with parallel substitutions (Casq1, Atp2a1, Myh2, Myl1) are expressed in the superfast sound-producing muscle of bats. Furthermore, we found that the calcium storage protein calsequestrin 1 of bats and dolphins functionally converged in its ability to form calcium-sequestering polymers at lower calcium concentrations, which may contribute to rapid calcium transients required for superfast muscle physiology. The proteins that our genomic screen detected could be involved in the convergent evolution of vocalization in echolocating mammals by potentially contributing to both rapid Ca2+ transients and increased shortening velocities in superfast muscles.\n\nAbbreviations

evolutionary biology↗

bioRxiv2017

BCL11A interacts with SOX2 to control the expression of epigenetic regulators in lung squamous cell carcinoma

Patients diagnosed with lung squamous cell carcinoma (LUSC) have limited targeted therapeutic options. We report here the identification and characterisation of the transcriptional regulator, BCL11A, as a LUSC oncogene. Analysis of cancer genomics datasets revealed BCL11A to be upregulated in LUSC but not lung adenocarcinoma (LUAD). We demonstrated that knockdown of BCL11A in LUSC cell lines abolished xenograft tumour growth and its overexpression in vivo led to lung airway hyperplasia and the development of reserve cell hyperplastic lesions. In addition, deletion of Bcl11a in the tracheal basal cells abolished the development of tracheosphere organoids while its overexpression led to solid tracheospheres with a squamous phenotype. At the molecular level we found BCL11A to be a target of SOX2 and we show that it is required for the oncogenic role of SOX2 in LUSC. Furthermore, we showed that BCL11A and SOX2 interact at the protein level and that together they co-regulated the expression of several transcription factors. We demonstrate that pharmacological inhibition of SETD8, a gene co-regulated by BCL11A and SOX2, alone or in combination with cisplatin treatment, shows significant selectivity to LUSC in comparison to LUAD cells. Collectively, these results indicate that the disruption of the BCL11A-SOX2 transcriptional program provides a future framework for the development of targeted therapeutic intervention for LUSC patients.

cancer biology↗

bioRxiv2017

Programming of macrophages by apoptotic cancer cells inhibits cancer progression through exosomal PTEN and PPARγ ligands

Apoptotic cell clearance by phagocytes is essential in tissue homeostasis. We demonstrated that conditioned medium (CM) from macrophages exposed to apoptotic cancer cells inhibits epithelial-mesenchymal transition (EMT), migration, and invasion of cancer cells with the acquisition of cancer-stem-like traits. Apoptotic 344SQ (ApoSQ) cell-induced PPAR{gamma} activity in macrophages caused increased PTEN levels, secreted in exosomes. ApoSQ-exposed CM from PTEN knockdown cells failed to enhance PTEN in recipient 344SQ cells, restore cellular polarity, and exert anti-EMT and anti-invasive effects. The CM which deficient of PPAR{gamma} ligands could not reverse the suppression of PPAR{gamma} activity and PTEN and consequently failed to the prevent EMT process. Moreover, single injection of ApoSQ cells inhibited lung metastasis in syngeneic mice with enhanced PPAR{gamma}/PTEN signaling both in tumor-associated macrophages and tumor cells. PPAR{gamma} antagonist GW9662 reversed PTEN signaling and anti-metastatic effect. Thus, apoptotic cancer cell therapy may offer a new strategy for the prevention of metastasis.

cancer biology↗

bioRxiv2017

H3K27me3-mediated silencing of Wilms Tumor 1 supports the proliferation of brain tumor cells harboring the H3.3K27M mutation

The lysine 27 to methionine mutation of histone H3.3 (H3.3K27M) is detected in over 75% of diffuse intrinsic pontine glioma (DIPG). The H3.3K27M mutant proteins inhibit H3K27 methyltransferase complex PRC2, resulting in a global reduction of tri-methylation of H3K27 (H3K27me3). Paradoxically, high levels of H3K27me3 were also detected at hundreds of genomic loci. However, it is not known how and why H3K27me3 is redistributed in DIPG cells. Here we show that lower levels of H3.3K27M mutant proteins at some genomic loci contribute to the retention of H3K27me3 peaks. But more importantly, Jarid2, a PRC2-associated protein, strongly correlates the presence of H3K27me3 and relieves the H3.3K27M-mediated inhibition in vivo and in vitro. Furthermore, we show that H3K27me3-mediated silencing of tumor suppressor gene Wilms Tumor 1 (WT1) supports the proliferation of DIPG cells and reaction of WT1 inhibits DIPG proliferation. Together, these studies reveal mechanisms whereby H3K27me3 is retained in the environment of global loss of this mark, and how persistence of this mark contributes to DIPG tumorigenesis.

cancer biology↗